Chiral phosphoric acid-catalyzed enantioselective three-component Povarov reaction using enecarbamates as dienophiles: Highly diastereo- and enantioselective synthesis of substituted 4-aminotetrahydroquinolines

Article abstract of DOI:10.1021/ja205891m

A chiral phosphoric acid (5)-catalyzed three-component Povarov reaction of aldehydes 2, anilines 3, and enecarbamates 4 afforded cis-4-amino-2-aryl(alkyl)- 1,2,3,4-tetrahydroquinolines 1 in high yields with excellent diastereoselectivities (>95%) and almost complete enantioselectivities (up to >99% ee). The reaction was applicable to a wide range of anilines bearing electron-donating (OMe) and electron-withdrawing groups (e.g., Cl, CF ₃, NO₂) and allowed, for the first time, aliphatic aldehydes to be employed in the enantioselective Povarov reaction. With β-substituted acyclic enecarbamates, 2,3,4-trisubstituted 1,2,3,4-tetrahydroquinolines with three contiguous stereogenic centers were produced in excellent diastereo- and enantioselectivities (87 to >99% ee). A detailed study of the active catalytic species allowed us to reduce the catalyst loading from 10% to 0.5% with no deterioration of enantiomeric excess. In addition, mechanistic studies allowed us to conclude unequivocally that the Povarov reaction involving enecarbamate as dienophile proceeded via a stepwise mechanism. The key role of the free NH function of the enecarbamate in the success of this transformation was demonstrated. NMR experiments indicating the catalyst-substrate interaction as well as a linear correlation between catalyst and product ee's were also documented.

Full text of DOI:10.1021/ja205891m

ARTICLE
pubs.acs.org/JACS
Chiral Phosphoric Acid-Catalyzed Enantioselective Three-Component
Povarov Reaction Using Enecarbamates as Dienophiles: Highly
Diastereo- and Enantioselective Synthesis of Substituted
4-Aminotetrahydroquinolines
Guillaume Dagousset,† Jieping Zhu,*,‡ and Gꢀeraldine Masson*,†
†Centre de Recherche de Gif, Institut de Chimie des Substances Naturelles, CNRS, 91198 Gif-sur-Yvette Cedex, France
‡Institute of Chemical Sciences and Engineering, Ecole Polytechnique Fꢀedꢀerale de Lausanne, EPFL-SB-ISIC-LSPN, CH-1015 Lausanne,
Switzerland
S Supporting Information
b
ABSTRACT: A chiral phosphoric acid (5)-catalyzed three-
component Povarov reaction of aldehydes 2, anilines 3, and
enecarbamates 4 afforded cis-4-amino-2-aryl(alkyl)-1,2,3,4-tet-
rahydroquinolines 1 in high yields with excellent diastereos-
electivities (>95%) and almost complete enantioselectivities
(up to >99% ee). The reaction was applicable to a wide range of
anilines bearing electron-donating (OMe) and electron-with-
drawing groups (e.g., Cl, CF3, NO2) and allowed, for the first
time, aliphatic aldehydes to be employed in the enantioselective Povarov reaction. With β-substituted acyclic enecarbamates, 2,3,4-
trisubstituted 1,2,3,4-tetrahydroquinolines with three contiguous stereogenic centers were produced in excellent diastereo- and
enantioselectivities (87 to >99% ee). A detailed study of the active catalytic species allowed us to reduce the catalyst loading from
10% to 0.5% with no deterioration of enantiomeric excess. In addition, mechanistic studies allowed us to conclude unequivocally
that the Povarov reaction involving enecarbamate as dienophile proceeded via a stepwise mechanism. The key role of the free NH
function of the enecarbamate in the success of this transformation was demonstrated. NMR experiments indicating the
catalystÀsubstrate interaction as well as a linear correlation between catalyst and product ee's were also documented.
’ INTRODUCTION
success. Kobayashi9 and Sundararajan10 disclosed the first examples
of enantioselective two-component Povarov reactions using chiral
BINOLÀytterbium and aminodiolÀtitanium(IV) complexes, re-
spectively, as catalysts. The enantioselectivities and application
scope of these two catalytic processes were nevertheless moderate.
A major breakthrough came from Akiyama’s group, who documen-
ted a phosphoric acid-catalyzed enantioselective Povarov reaction of
vinyl ethers and N-arylimines derived from o-hydroxyanilines.
Although the Povarov adducts were generally obtained with ex-
cellent diastereoselectivities and enantiomeric excesses (ee's) under
Akiyama’s conditions, the necessity of using o-hydroxyaniline as one
of the reaction partners limited the access to only 8-hydroxytetrahy-
droquinoline derivatives.11 In addition, only imine-derived aromatic
aldehydes were accepted as substrates in all these catalytic enantio-
selective processes.9,11
Tetrahydroquinoline is a key structural unit found in many
biologically active natural products1 and synthetic pharmaceutical
agents.1a,2 In particular, 4-amino-1,2,3,4-tetrahydroquinolines3 re-
present an important subclass of this family which has been found in
natural products such as martinellic acid,4 a potent bradykinin
antagonist. It has also displayed an excellent track record in
medicinal chemistry, the notable examples being torcetrapib (CP-
529,414, Pfizer),5 a potent and first cholesteryl ester transfer protein
inhibitor, and (À)-L-689,560,6 a potent antagonist at the N-methyl-
D-aspartate receptor glycine site (Figure 1).
Consequently, the development of new synthetic routes to
tetrahydroquinolines has been actively investigated in recent years.7
Among many reported methods for the construction of polysub-
stituted tetrahydroquinolines, the Povarov reaction,8 an inverse
electron-demand aza-DielsÀAlder (IEDDA) reaction between
2-azadienes and electron-rich olefins catalyzed by either protic or
Lewis acids, stood out as one of the most attractive. Since most of
the tetrahydroquinoline-containing natural products and drug can-
didates contain stereogenic center(s), the ability to render the
Povarov reaction enantioselective is of significant importance.
However, despite efforts dedicated to this goal, the development
of an enantioselective Povarov reaction met with only limited
In 2009, we reported the first example of a three-component
enantioselective Povarov reaction for the synthesis of 4-amino-
1,2,3,4-tetrahydroquinolines (1, Scheme 1). The reaction of
aldehydes 2, anilines 3, and enecarbamates 4 in the presence of
a catalytic amount of chiral phosphoric acid 5 furnished
Received: June 24, 2011
Published: August 10, 2011
r
2011 American Chemical Society
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Figure 1. Selected examples of bioactive 4-aminotetrahydroquinolines.
Scheme 1. Catalytic Enantioselective Povarov Three-
Component Synthesis of 2,4-Disubstituted 1,2,3,4-
Tetrahydroquinolines
Scheme 2. Enantioselective Synthesis of 2,3,4-Trisubstituted
1,2,3,4-Tetrahydroquinolines
experiments, linear correlation between catalyst and product ee's,
and mechanistic studies as well as a rationale for the stereochem-
ical outcome of this transformation.
’ RESULTS AND DISCUSSION
In our preliminary communication, we demonstrated that the
chiral phosphoric acid derived from octahydro-(R)-BINOL 5
(see Supporting Information for details) was able to efficiently
promote the enantioselective three-component Povarov reaction
between aldehydes 2, anilines 3, and benzyl N-vinylcarbamate
(4a).8,19,20 A wide range of electron-neutral, -rich, and -poor
aromatic aldehydes were appropriate substrates, affording cis-2,4-
disubstituted 4-aminotetrahydroquinolines 121 with both high
enantioselectivities (98 to >99% ee) and diastereoselectivities
(>95:5 dr).12 Remarkably, the optimized reaction conditions
were also applicable to aliphatic aldehydes. Both R- and β-
branched aldehydes participated effectively in the three-compo-
nent reaction (Supporting Information). On the other hand,
linear aldehydes gave lower yields due to the competitive
isomerization of the in situ formed aliphatic N-arylimines to
the corresponding enamines.4,22,24 However, we were pleased to
find that when the reaction was carried out at À30 °C, the
expected cycladducts were isolated in good yields with high ee's
(Supporting Information).12 A wide range of anilines were also
suitable partners to afford the corresponding cycloadducts in
good to high yields and excellent enantioselectivities (up to 99%
ee). However, in our previous report, when anilines with strong
electron-withdrawing substituents such as 4-trifluoromethyl
were subjected to the same conditions, moderate yields were
observed. Thus, we decided to reinvestigate the reaction with
4-trifluoromethylaniline. Fortunately, by simply increasing the
reaction time from 1 to 12 h, the yield of tetrahydroquinoline was
significantly enhanced (Supporting Information). This modifica-
tion increased the overall yield of our original synthesis of
torcetrapib from 32 to 40%.12
4-amino-1,2,3,4-tetrahydroquinolines 1 in good to high yields with
excellent diastereo- (up to >99:1) and enantioselectivities (up to
>99% ee).12 Importantly, the aliphatic N-arylimines generated
in situ were successfully employed in the enantioselective Povarov
reaction for the first time. The use of benzyl N-vinylcarbamate
(4a) possessing the free NH function as dienophile13,14 allowed us
to use simple anilines, instead ofo-hydroxyanilines, givingaccessto
structurally diverse tetrahydroquinolines 1.
Subsequent to our initial disclosure, Gong reported a three-
component synthesis of the tricyclic ring system julolidine by
combining the enantioselective Povarov reaction with the in-
tramolecular hydroamination reaction.15 Ricci et al.16 and Feng
et al.17 described two catalytic asymmetric IEDDA reactions
employing vinylindoles and cyclopentadiene, respectively, as
dienophiles. Jacobsen et al. developed an efficient asymmetric
two-component Povarov reaction using 2,3-dihydrofuran, vinyl-
lactam, and N-Cbz-2,3-dihydropyrrole as dienophiles in the
presence of a dual chiralÀachiral acid catalytic system.18
Despite this significant progress, enantioselective access to
2,3,4-trisubstituted tetrahydroquinolines via the Povarov reac-
tion was restricted to cyclic dienophiles.9,1718 To the best of our
knowledge, there is no convenient method for the preparation of
4-amino-1,2,3,4-tetrahydroquinolines 1 with various substitution
patterns at C-2, C-3, and C-4. In this paper, we briefly summarize
our previous studies on the Brønsted acid-catalyzed enantiose-
lective three-component Povarov reaction for the synthesis of
highly substituted 4-aminotetrahydroquinolines. The use of
β-substituted acyclic enecarbamates as a key reaction partner
allowed us to access for the first time the enantiomerically
enriched 2,3-disubstituted 4-amino-1,2,3,4-tetrahydroquinolines
1 (Scheme 2). We also detail control experiments, NMR titration
Having succeeded in the elaboration of optically enriched cis-
2,4-disubstituted-1,2,3,4-tetrahydroquinolines (see Supporting
Information for details), we next investigated the use of β-
substituted enecarbamates as nucleophiles in order to generate
three adjacent stereogenic centers in one operation. As the
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Scheme 3. Povarov Reaction of β-Substituted Acyclic
Enecarbamates (E)-4b and (Z)-4b
enantioselectivities. As previously described,12 when a meta-
substituted aniline, such as 3-iodoaniline (3c, entry 10), was
used, two regioisomers, 7-iodo-1k and 5-iodo-1k, were iso-
lated, with the sterically more congested isomer 5-iodo-1k
being the major one. To evaluate the influence of the sub-
stituent at the C-2 position of the double bond, a series of
enecarbamates, bearing propyl (4c), isopropyl (4d), and tert-
butyldiphenylsilyloxypropyl (4e) substituents, were prepared
and were subjected to reaction with benzaldehyde (2a) and
4-methoxyaniline (3a) under our optimized conditions. With
4c and 4e, yields and selectivities were high and were compar-
able to those obtained with (E)-4b. A lower yield but still good
enantioselectivity were obtained with the bulkier (E)-benzyl
3-methylbut-1-enylcarbamate 4d (entry 11).
Although the enantiomeric excess and yield were reliable, we
found that time needed to complete the reaction varied (ranging
from 1 to 12 h) depending on the batch of chiral phosphoric acid
5 used, as was observed earlier by Ding et al.25 Recently Ishihara
et al. and List et al. demonstrated that purification of chiral
phosphoric acids by silica gel chromatography can result in the
formation of a variable amount of alkali or alkaline earth
metalÀphosphoric acid complexes.26 The formation of these
phosphate salts could explain the variation of reaction rates in
these chemical reactions. Indeed, when 5 washed with HCl was
used, the 4-aminotetrahydroquinolines 1 were systematically
obtained after 1 h.27 As metal phosphate salts were known to
create a well-defined chiral environment and could even, in
certain cases, reverse the enantiofacial selectivities relative to
the free phosphoric acids,28 we decided to evaluate their catalytic
power in the enantioselective Povarov reaction. Surprisingly, no
reaction occurred when calcium bis(phosphate) complex Ca-
(5)2, instead of 5, was used as catalyst under otherwise identical
conditions. This demonstrated that only metal-free chiral phos-
phoric acid was an effective catalyst for the present Povarov
reaction. On the basis of this observation, we reasoned that it
might be possible to reduce the catalyst loadings without
significantly affecting the catalytic activity and the enantioselec-
tivity by using acid-washed phosphoric acid. The results are
summarized in Table 2. It was found that, with 0.5 mol % of 5,
reaction of 2a, 3a, and (E)-4b afforded 1a in 80% yield with 96%
ee, albeit with a longer reaction time (12 h). In terms of
operational convenience, the use of 2.5 mol % phosphoric acid
5 at 0 °C ensured high levels of reaction efficiency and enantios-
electivity while maintaining the expedient reaction time.
The mechanism of the Povarov reaction has long been a topic
of controversy.29 Several recent theoretical studies indicated that
the mechanism can be concerted or stepwise, depending on the
dienophiles used. In our case, the polarized nature of the
enecarbamate double bond led us to speculate that a stepwise
mechanism initiated by the Mannich reaction might be predo-
minant. If this pathway were indeed operating, it would then be
possible to trap the N-acyliminium intermediate generated after
the Mannich reaction by an external nucleophile. To verify this
working hypothesis, a series of control experiments were per-
formed. Reaction of benzaldehyde (2a), 4-methoxyaniline (3a),
and enecarbamate 4a in the presence of 5 and EtOH (17 equiv)
afforded indeed the Mannich adduct 6a in 21% yield, together
with the tetrahydroquinoline 1 (50%). With aniline (3d) and
electron-poor anilines such as 4-chloroaniline (3e) and 4-nitroa-
niline (3b) under otherwise identical conditions, only the
Mannich adducts were isolated, at the expense of the Povarov
products (Table 3). These results not only provided direct
geometry of the dienophile can impact the stereochemical out-
come of the reaction, we decided to test the benzylprop-1-
enylcarbamates (E)-4b and (Z)-4b separately. Pleasingly, the
three-component reaction using (E)-benzylprop-1-enylcarba-
mate (E)-4b, benzaldehyde (2a), and 4-methoxyaniline (3a)
under our standard conditions afforded the desired tetrahydro-
quinoline (trans-1a, all-trans) in 94% yield with excellent enantio-
and diastereoselectivity (eq 1, Scheme 3). On the other hand, the
(Z)-enecarbamate (Z)-4b was much less reactive than its E
counterpart, affording 1a in 32% yield as a mixture of two
separable diastereoisomers (trans:cis = 9:1). Surprisingly, the
major product isolated from the reaction of (Z)-4b was found to
be the same (all-trans) as that derived from (E)-4b (eq 2,
Scheme 3). We assumed that, in the presence of phosphoric
acid, a slow Z/E isomerization of enecarbamate (Z)-4b to (E)-4b
via the N-acyliminium intermediate occurred before the Mannich
reaction. The subsequent reaction of (E)-4b with 2a and 3a gave
trans-1a as a major product. It is also interesting to note that,
while the trans isomer 1a was obtained in 90% ee, cis-1a was
isolated in a much lower ee (63%). The trans relative stereo-
chemistry between C-2 and C-3 and between C-3 and C-4 in 1a
was established by NOESY experiments (Scheme 3).
Encouraged by the high levels of diastereo- and enantios-
electivity observed in the reaction of (E)-4b, we next examined
the scope of this reaction by varying the structure of aldehydes
(Table 1). A variety of aromatic aldehydes, ranging from
electron-rich substrates [3-methoxybenzaldehyde (2b), fural-
dehyde (2e)] to electron-poor aromatic aldehydes [4-nitro-
benzaldehyde (2c)], underwent reaction with (E)-4b and
4-methoxyaniline (3a) without event to afford the correspond-
ing tetrahydroquinolines in good yields with excellent enan-
tioselectivities (entries 1, 2, and 4). Ortho-substituted aromatic
aldehydes such as 2-bromobenzaldehyde (2d) and cinnamal-
dehyde (2f) required longer times (12 h) to drive the reaction
to completion (entries 2 and 5). R-Substituted aliphatic
aldehydes (entry 6) also performed well under the standard
reaction conditions, although reactions with linear aldehydes
(entries 7 and 8) had to be carried out at À30 °C to avoid
undesired isomerization of the imine intermediate and
enecarbamate.4,22,24 Anilines having electron-donating (4-
methoxy), -neutral (H, entry 11, Table 1), and -withdrawing
groups (4-nitro, entry 9) were suitable reaction partners to
afford the corresponding adducts in high yields and excellent
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Table 1. Scope of the Enantioselective Brønsted Acid-Catalyzed Three-Component Povarov Reaction with β-Substituted
(E)-Enecarbamatesa
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Table 1. Continued
a General conditions: aldehyde (0.10 mmol), amine (0,10 mmol), β-substituted enecarbamate (0.11 mmol), and 5 (0.01 mmol) in CH2Cl2 (1.0 mL) at
0 °C during 1 h. b Yields refer to chromatographically pure product. c Enantiomeric excess was determined by enantiodiscriminating HPLC analysis.
d 12 h reaction time. e Reaction performed at À30 °C.
Table 3. Interrupted Povarov Cycloadditiona
Table 2. Optimization of Catalyst Loadinga
catalyst loading
(mol %)
time
(h)
yield
(%)b
ee
(%)c
yield (%)b
entry
entry
R1
6
1
1
2
3
4
5
10
1
3
94
78
81
80
16
96
96
96
96
96
2.50
1
1
2
3
4
MeO (3a)
H (3d)
21 (6a)
77 (6b)
85 (6c)
72 (6d)
50
11
À
12
12
72
0.5
Cl (3e)
0.1
NO2 (3b)
À
a General conditions: aldehyde (0.10 mmol), amine (0.10 mmol),
benzyl N-vinylcarbamate (0.11 mmol), and 5 in CH2Cl2 (1.0 mL) at
0 °C. b Yields refer to chromatographically pure product. c Enantiomeric
excess was determined by enantiodiscriminating HPLC analysis.
a General conditions: aldehyde (0.10 mmol), amine (0,10 mmol),
benzyl vinylcarbamate (0.11 mmol), ethanol (1.7 mmol), and 5 (0.01
mmol) in CH2Cl2 (1.0 mL) at 0 °C. b Yields refer to chromatographi-
cally pure product.
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evidence of a stepwise mechanism of our catalytic enantiose-
lective Povarov reaction but also allowed us to develop an
efficient enantioselective synthesis of 1,3-diamine via a one-
pot Mannich reaction/reduction process.14f The interrupted
Povarov reaction was previously elegantly exploited by Lavilla
and co-workers for the synthesis of heterocycles other than
tetrahydroquinolines.30
Dual activation of the imine and secondary enecarbamate by
bifunctional chiral phosphoric acid catalysis was our working
hypothesis for the development of the present transformation.12,14
To gain insight into this mechanistic assumption, we decided to
evaluate the influence of the free NH function of carbamate on the
enantioselectivity of the transformation. Tertiary enecarbamates
such asbenzylN-methyl-N-vinylcarbamate (4f), 3-vinyloxazolidin-
2-one (4g), and N-Cbz-2-pyrroline (4h) were synthesized and
tested in the three-component reaction with 2a and 3a (Figure 2).
With acyclic enecarbamates 4f and 4g, no reaction took place,
while with the cyclic enecarbamate 4h, the corresponding endo
cycloadduct 1p (dr >99/1) was isolated in 30% yield with only
25% ee (Figure 2). These results indicated clearly that the NH
moiety of 4aÀe plays an important role, not only for the
enantioselectivity but also for the reactivity.31
To probe the nature of the catalystÀsubstrate interaction,32,33
titration of imine 7 with phosphoric acid by 1H NMR spectros-
copy was performed.34 When 1 equiv of phosphoric acid 5 was
used, a significant downfield shift of aldimine proton (Δδ = 1.6
ppm) was observed, indicating the association of these two
species (Figure 3).35 When 2 equiv of phosphoric acid 5 was
used, 7 was found to exist as a single associated form, 5-7. Recent
NMR studies from Gschwind, Rueping and co-workers using
15N-labeled imines concluded that, while ion-pairing is the
predominant interaction between diphenylphosphate and (E)-
N-(4-methylbenzylidene)aniline, H-bonding between imines
(especially those with less basic one) and phosphoric acids could
also contribute to the activation of imines.36 While our titration
experiments could not allow us to distinguish these two activa-
tion modes, we would favor the ion-paring activation mode in our
case on the basis of the fact that imine 7 has a basic nitrogen atom.
This hypothesis was also reinforced by the absence of a nonlinear
effect under our conditions (vide infra).
Gong and co-workers recently demonstrated that phosphoric
acids can exist as aggregates both in solution and in the solid
state.37 They also provided evidence of asymmetric amplification
of certain phosphoric acid-catalyzed reactions, especially those
involving nonbasic N-acylated imines as electrophiles. This
observation prompted us to investigate the relationship between
the optical purity of the phosphoric acid catalyst 5 and that of the
Figure 2. Povarov reaction of tertiary enecarbamates.
Figure 3. NMR spectra of titration experiments (500 MHz, CDCl3).
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Figure 4. Correlation between the enantiomeric excess of 5 and that of product trans-1a.
Scheme 4. Proposed Mechanism and Stereochemical Issue
Scheme 5. Akiyama’s Stereochemical Model
tetrahydroquinoline trans-1a under our optimal conditions. As
shown in Figure 4, the ee of the tetrahydroquinoline trans-1a is
nearly proportional to that of the chiral phosphoric acid 5,
indicating the absence of a nonlinear effect.38 We therefore
assumed that a single catalyst molecule was involved in the
activation of imine in the key Mannich addition step.
Figure 5. Simꢀon and Goodman’s model.
were derived from (R)-BINOL. The reversal of enantiofacial
selectivity could be accounted for by the difference in H-bonding
models. In Akiyama’s catalytic system, the phosphoric acid
activated only the electrophile via the participation of the
o-hydroxy group.11 The Re-face attack of the enol ether onto imine
via transition state 11 would then afford the tetrahydroquinoline
12 (Scheme 5).
Evidence that both activation modes via transition states 9 and
11 could be operating was obtained by using the o-hydroxyani-
line (3e) in the Povarov reaction. Reaction of 3e with benzalde-
hyde (2a) and enecarbamate 4a afforded the corresponding
tetrahydroquinoline 1q in 64% yield with 71% ee. A possible
competition between our dual activation model and Akiyama’s
model could account for the diminished ee of product 1q.
On the basis of the results of their DFT calculation, Simꢀon and
Goodman proposed a model, 13, to account for the stereochemical
outcome of the Mannich reaction that we observed experimentally
On the basis of these observations, we assumed that the
phosphoric acid-catalyzed three-component Povarov reaction
proceeded via protonation of the imine, forming chiral ion pair
8, followed by hydrogen-bonding between the enecarbamate NH
and the Lewis basic phosphoryl oxygen. A pseudo-intramolecular
Si-face attack of (E)-enecarbamate on the iminium carbon of the
chiral contact ion pairs via transition state 9 would then afford
iminium 10, with concurrent proton shift within the phosphoric
acid sphere. Finally, an intramolecular aza-FriedelÀCrafts reac-
tion via the sterically less congested conformer 10 would furnish
the observed 2,4-cis-substituted tetrahydroquinoline 1 with
defined absolute configuration, as shown in Scheme 4. It is
interesting to note that the absolute configuration of tetrahy-
droquinoline 1 we obtained is different from that obtained by
Akiyama, although the chiral phosphoric acids used in both cases
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(Figure 5).39,40 Although the significant difference in the reactivity
observed between Z- and E-isomers 4b has yet to be explained, a
transition state, 14 (Figure 5), displaying unfavorable interactions
between the (Z)-enecarbamate and the ion-pair complex of the
imine and 5, could potentially explain the low reactivity of the
(Z)-enecarbamate.
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’ CONCLUSION
We reported the first catalytic enantioselective three-com-
ponent Povarov reaction of aldehydes 2, anilines 3, and
enecarbamates 4 to furnish cis-1-aryl(alkyl)-4-aminotetrahy-
droquinolines 1 in good yields with excellent diastereo- and
enantioselectivities (up to 98% ee). The use of acyclic
β-substituted enecarbamates in this reaction allowed us to access
the 2,3,4-trisubstituted 1,2,3,4-tetrahydroquinolines with three
contiguous stereogenic centers, again with high diastereoselec-
tivities and excellent enantioselectivities. A study on active
catalytic species demonstrated that only the free phosphoric acid
catalyzed the Povarov reaction. These findings allowed us to
reduce the catalyst loading by a factor of 20, to as little as 0.5 mol
%. The trapping experiments provided sound evidence that the
present Povarov reaction involving enecarbamate proceeded via
a stepwise mechanism. Mechanistic investigations including
NMR spectroscopy studies, linear effects, and control experi-
ments highlighted the crucial role played by the activation of
the imine via ion-pairing and the enecarbamate via H-bonding
with bifunctional phosphoric acid catalyst. The low catalyst
loading, excellent yields and enantioselectivities, and operational
simplicity make our catalytic system attractive for the syn-
thesis of highly functionalized, enantiomerically enriched
4-aminotetrahydroquinolines.
’ EXPERIMENTAL SECTION
General Procedure for the Catalytic Enantioselective
Three-Component Povarov Reaction. To a solution of aldehyde
(2, 0.1 mmol) in dry CH2Cl2 (0.4 mL) at room temperature was added
aniline (3, 0.1 mmol). After being stirred at room temperature for
30 min, the reaction mixture was cooled to 0 °C, and a solution of
phosphoric acid catalyst (5, 0.01 mmol) and enecarbamate (4, 0.11
mmol) in CH2Cl2 (0.3 mL) was added. The resulting solution was
stirred under an argon atmosphere at 0 °C for 1 h. Solvents were
removed in vacuo, and the residue was purified by flash chromatography
on silica gel (heptane/EtOAc) to afford the corresponding 4-amino-
1,2,3,4-tetrahydroquinoline.
’ ASSOCIATED CONTENT
S
Supporting Information. Experimental details, charac-
b
terization of new compounds, and selected NMR and HPLC
spectra. This material is available free of charge via the Internet
at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
jieping.zhu@epfl.ch; masson@icsn.cnrs-gif.fr
’ ACKNOWLEDGMENT
We thank CNRS for financial support. G.D. thanks MESR for
a doctoral fellowship.
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Journal of the American Chemical Society
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