Highly enantioselective assembly of functionalized tetrahydroquinolines with creation of an all-carbon quaternary center

Article abstract of DOI:10.1002/chem.201103136

A Mannich-Michael combo: An efficient and highly enantioselective cascade process by H-bonding catalysis for the synthesis of functionalized tetrahydroquinolines has been developed. An indane amine-thiourea small molecule has been discovered to catalyze this process in high yields and with good diastereomeric ratios and excellent enantioselectivities (see scheme). Copyright

Full text of DOI:10.1002/chem.201103136

COMMUNICATION
DOI: 10.1002/chem.201103136
Highly Enantioselective Assembly of Functionalized Tetrahydroquinolines
with Creation of an All-Carbon Quaternary Center
Hao Rui Tan,[a] Hui Fen Ng,[a] Jun Chang,[b] and Jian Wang*[a]
Over the past few decades, natural products have proven
to be useful small molecule probes in the medicinal chemis-
try community.[1] A rapid access to small molecules that are
guided by natural products appears to be quintessential for
the success of chemical genetics/genomics-based programs.
The design and synthesis of novel scaffolds as chiral core
structures for the library generation of natural-product-like
derivatives is an essential step in accessing a wide range of
structural complexes in an efficient manner.[2]
Tetrahydroquinolines, considered to be valuable building
blocks, have attracted considerable attention from organic
and medicinal chemists, primarily because they display a va-
riety of physiological activities.[3] Several derivatives have
been found to elicit potent biological responses, leading to
analgesic, antiarrhythmic, cardiovascular, immunosuppres-
sant, antitumor, antiallergenic, anticonvulsant, and antifertil-
ity-antagonist activities.[4] Some tetrahydroquinolines have
also been found to be pesticides, antioxidants, photosensitiz-
ers, and dyes.[3d] In addition, the chiral tetrahydroquinoline
scaffold is discovered in a number of important pharmaceut-
ical compounds, as exemplified by (+)-cuspareine,[5] (+)-ga-
lipinine,[5a,6] (+)-angustureine,[6] martinellic acid,[7] martinel-
line,[7] an anticancer agent,[8] and an antihyperalgesic agent[9]
(Figure 1).
Based on the broad biological application of the tetrahy-
droquinoline family, we wondered whether it would be pos-
sible to efficiently assemble a highly substituted tetrahydro-
quinoline skeleton. Although a number of strategies have
been developed for the synthesis of this skeleton, methods
for the formation of chiral tetrahydroquinolines mainly rely
on the asymmetric hydrogenation of the corresponding
quinoline derivatives by using chiral metal catalysts or chiral
Brønsted acids.[10] Another popular method used to access
the tetrahydroquinoline scaffold is the nucleophilic addition
of imines.[11] However, organocatalytic examples have been
Figure 1. Examples of chiral tetrahydroquinolines as pharmaceutical
drugs.
rarely reported, even though organocatalysis has become
a rapidly emerging field. In 2003, Jørgensen and co-workers
reported the first Michael addition of malonates to a,b-un-
saturated enones [Eq. (1)].[12] The resulted Michael adducts
were transferred to chiral tetrahydroquinolines by a sequen-
tial hydrogenation step. Later on, Rueping and co-workers
reported a different organocatalytic strategy; the direct
transfer hydrogenation of quinolines catalyzed by a chiral
phosphoric acid [Eq. (2)].[13] In 2008, the Fustero group dis-
closed a highly enantioselective intramolecular Michael ad-
dition to construct the chiral tetrahydroquinoline scaffold by
using a diarylprolinol catalyst [Eq. (3)].[14] Most recently,
Akiyama reported a chiral phosphoric acid catalyzed redox
process, which could generate the tetrahydroquinoline scaf-
fold in high yields and excellent stereoselection [Eq. (4)].[15]
Furthermore, a relay catalytic strategy, a Povarov reaction,
and several other methods were also applied to efficiently
synthesize the chiral tetrahydroquinoline scaffold.[16]
[a] H. R. Tan, H. F. Ng, Prof. Dr. J. Wang
Department of Chemistry, National University of Singapore
3 Science Drive 3, Singapore 117543 (Singapore)
Fax : (+65)6516-1691
E-mail: chmwangj@nus.edu.sg
[b] Dr. J. Chang
School of Pharmacy, Fudan University
826 Zhangheng Road
Shanghai 201203 (P. R. China)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201103136.
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Scheme 1. Investigation of the reaction outcome. The ratio of products
was determined by H NMR spectroscopy.
Malononitrile is a valuable and unique donor in conjugate
addition reactions. Recently, our research group[20d] and
others[17] have reported a wide range of asymmetric organo-
catalytic conjugate additions, which employed malononitrile
as nucleophile. We envisioned that an organocatalytic conju-
gate addition of malononitrile to 2-alkenyl substituted
imines and a subsequent conjugate addition might provide
a viable approach for the construction of optically enriched
highly substituted tetrahydroquinolines, which are known to
be important structural elements in many biologically active
compounds and natural products (Figure 1). Herein, we
document the first highly stereoselective cascade Mannich–
Michael addition of malononitrile to 2-alkenyl substituted
imines, leading to an enantioselective preparation of highly
substituted tetrahydroquinolines bearing an all-carbon qua-
ternary center [Eq. (5)].[22] Undoubtedly, this strategy allows
a quick assembly of diversely functionalized tetrahydroqui-
nolines under mild reaction conditions. Both excellent enan-
tioselectivities and high to excellent yields can be achieved,
thereby giving a straightforward access to optically pure tet-
rahydroquinolines.
1
Unfortunately, we failed to seek a successful method to syn-
thesize this special (E)-2-(2-nitrovinyl) aniline (Scheme 1,
X=NO2). To achieve a high yield of the desired compound
c, we wondered whether the preformation of the 2-alkenyl-
substituted imine (Scheme 1, compound a) could trigger the
cascade Mannich–Michael process to efficiently generate
the desired tetrahydroquinoline c. Gratifyingly, the investi-
gation showed that the desired tetrahydroquinoline c was ef-
ficiently resembled (Scheme 1, a/b/c=<5:0:95). Meanwhile,
we did not find any Knoevenagel condensation product
(Scheme 1, compound b). In this process, the starting mate-
rial (compound a) was also completely converted to the de-
sired tetrahydroquinoline (compound c).
With this finding in hand, we started to probe the asym-
metric catalytic feasibility of this cascade Mannich–Michael
process. To conduct a stereoselective cascade Mannich–Mi-
chael process of malononitrile (2a) to (E)-3-{2-[(E)-benzyli-
deneamino]phenyl}-1-phenylprop-2-en-1-one (1a, preformed
imine), a bifunctional tertiary amine catalyst with a Brønsted
acid moiety would be a suitable choice. Then, we started the
catalyst investigation (Figure 2). As shown in Table 1, the
quinine-thiourea catalyst II, developed by the Soꢁs,
Connon, and Dixon groups,[18] was found to be a poor cata-
lyst and gave 88% yield in 24 h with À25% ee and 2.3:1 d.r.
We began our investigation by examining the triethyl-
amine (TEA)-catalyzed three-component reaction of 2-al-
kenyl-substituted aniline, benzaldehyde, and malononitrile.
The initial experimental results showed that the use of a cat-
alytic amount of triethylamine enabled a reaction between
the 2-alkenyl-substituted aniline, benzaldehyde, and malono-
nitrile. Surprisingly, if an ester group was introduced to the
2-alkenyl-substituted aniline, an unexpected compound
a (an intermediate of the desired compound c) was generat-
ed in 24 h (Scheme 1, a>95%). Then, we tried a stronger
electron-withdrawing group, phenyl ketone (Scheme 1, X=
COPh). However, a mixture of compound a and c was gen-
erated (Scheme 1, a/c=90:10). Inspired by this finding
(about 10% formation of c), we deduced that the electron-
withdrawing group might accelerate the Mannich reaction
to form the desired product c. Undoubtedly, the nitro group
is an ideal example of a strong electron-withdrawing group.
Figure 2. Investigated organocatalysts I–V.
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Functionalized Tetrahydroquinolines
COMMUNICATION
Table 1. Evaluation of chiral organocatalysts.[a]
Table 2. Optimization of other reaction parameters.[a]
Yield [%][b]
d.r.[c]
ee [%][d]
Entry
Cat.
t [h]
Yield [%][b]
d.r.[c]
ee [%][d]
Entry
Solvent
T [8C]
t [h]
1
2
3
4
I
18
24
24
12
12
24
95
88
94
90
92
85
2.9:1
2.3:1
3.1:1
3.3:1
3.1:1
3.0:1
56
À25
À63
75
85
85
1
2
3
4
5
C2H4Cl2
CHCl3
toluene
PhCF3
xylenes
xylenes
xylenes
xylenes
Et2O
RT
RT
RT
RT
RT
0
RT
RT
RT
RT
RT
12
12
12
12
12
24
24
12
24
24
24
93
97
95
94
97
97
97
97
95
87
88
5.1:1
4.8:1
5.6:1
6.2:1
7.5:1
7.5:1
7.0:1
6.8:1
6.1:1
2.8:1
2.9:1
86
90
99
97
>99
96
92
92
85
0
II
III
IV
V
V
5
6[e]
6
7[e]
8[f]
9
[a] Reaction conditions: CH2Cl2 (0.4 mL), 1a (0.08 mmol, 1.0 equiv), 2a
(0.16 mmol, 2.0 equiv), 4 ꢃ MS (20 mg), and catalyst (10 mol%) at room
temperature. [b] Yield of isolated product after column chromatography.
[c] Diastereomeric ratio. [d] Enantiomeric excess (ee) was determined by
HPLC. [e] Molecular sieves (MS) were not used.
10
11
DMF
iPrOH
0
[a] Unless specified, see the Experimental Section for reaction conditions.
[b] Yield of isolated product after column chromatography. [c] Diastereo-
meric ratio. [d] Enantiomeric excess (ee) was determined by HPLC. [e] A
catalyst loading of 5 mol% was used. [f] 2a (4 equiv) was used.
(Table 1, entry 2). Catalyst I (Takemotoꢂs thiourea)[19] also
only offered a 2.9:1 d.r. and moderate 56% ee (Table 1,
entry 1). Consequently, the discovery of a novel and active
chiral catalyst, which could promote this reaction with both
high efficiency and excellent stereocontrol, became our
main focus. In this context, we sought to extent the usage of
the indane amine-thiourea catalytic system that was devel-
oped in our group.[20] Undoubtedly, the bifunctional indane
amine-thiourea organocatalysts demonstrated some unique
aspects, such as higher activity and a flexible dihedral angel
for stereocontrol. Catalyst V, a member of indane-thiourea
catalysts, provided a much better result (Table 1, entry 5;
92% yield, 85% ee, 3.1:1 d.r.). The examination of other
indane-thiourea catalysts showed that no further
the generality of our cascade process, concentrating first on
the 2-substituted imine starting material (Table 3, 1a–p).
The reactions proceeded smoothly with various aromatic R1
groups. Both electron-withdrawing (Table 3, entries 2 and 3)
and electron-donating substituents (Table 3, entries 4 and 5)
on R1 could be applied to this transformation; the substitu-
tion pattern of the arene only had limited influence on the
enantioselectivity of the reaction. For the R2 group, the re-
action proceeded fast with electron-deficient substituents
improvement of the stereoselectivity could be ach-
ieved. Finally, catalyst V was selected as ideal cata-
lyst for further optimization.
Table 3. Substrate scope of 2-substituted imines.[a]
To achieve a higher stereoselectivity, we did fur-
ther investigations on other parameters, such as sol-
vent and reaction temperature. The results showed
that less polar solvents were generally essential for
a high stereoselectivity. High enantioselectivities of
tetrahydroquinoline 3a were observed in chlorinat-
ed (C2H4Cl2, CHCl3; Table 2, entries 1 and 2), ether
(Et2O; Table 2, entry 9), and aromatic solvents (tol-
uene, PhCF3, and xylenes; Table 2, entries 3–8). For
high polar solvents, lower enantioselectivities were
obtained, owing to a potential destroy of H-bonding
interactions by the polar solvents (Table 2, en-
tries 10 and 11; 0% ee). Finally, the solvent xylenes
were found to be an ideal reaction medium
(Table 2, entry 5; 97% yield, >99% ee, 7.5:1 d.r.).
To further improve the diastereoselectivity, we also
examined the reaction temperature and the catalyst
loading. The results indicated that no obvious en-
hancement of the diastereoselectivity was observed
(Table 2, entries 6–8).
Entry
Y
R1
R2
t
Yield d.r. [c] ee
[h] [%][b]
[%][d]
1
2
3
4
5
6
7
8
9
10
11
12
13[e]
14
15
16
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Ph (3a)
Ph
Ph
Ph
Ph
10 97
12 92
12 96
10 90
15 93
10 94
12 96
12 96
15 90
22 91
16 90
14 95
7.5:1
8.0:1
9.8:1
7.8:1
9.9:1
7.2:1
9.6:1
7.5:1
6.7:1
6.8:1
7.7:1
8.1:1
6.3:1
2.2:1
5.2:1
7.0:1
>99
97
96
96
94
99
98
95
99
95
96
98
92
99
92
97
4-ClC6H4 (3b)
4-BrC6H4 (3c)
4-MeC6H4 (3d)
3,4-(OCH2O)C6H4 (3e) Ph
Ph (3 f)
Ph (3g)
Ph (3h)
Ph (3i)
Ph (3j)
Ph (3k)
Ph (3l)
Ph (3m)
Ph (3n)
Ph (3o)
4-ClC6H4
2-ClC6H4
3,4-Cl2C6H3
4-MeOC6H4
4-BnOC6H4
4-iPrC6H4
2-thiophene
1-naphthalene 26 88
CH=CHC6H5
CO2Et
Ph
12 94
12 94
12 97
5-Cl Ph (3p)
[a] Unless specified, see the Experimental Section for reaction conditions. [b] Yield of
isolated product after column chromatography. [c] Diastereomeric ratio. [d] Enantio-
Having established an efficient protocol for the
cascade reaction of 1a and 2a, we then examined meric excess (ee) was determined by HPLC. [e] Reaction was performed at 08C.
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3867

J. Wang et al.
(Table 3, entries 6–8), as well as electron-rich substituents
(Table 3, entries 9–11). The substitution pattern of R2 was
also observed to have a limited effect on the stereoselectiv-
ity and reaction rate. If a heterocyclic ring was introduced
to the R2 position, the reaction still proceeded well (Table 3,
entry 12; 98% ee, 8.1:1 d.r.). An alkenyl or ester group
could also be introduced to the R2 position and afforded
good stereocontrol (Table 3, entries 14 and 15; 99 and
92% ee, 2.2:1 and 5.2:1 d.r., respectively). In addition, it was
possible to introduce other substituents, such as Y=5-Cl, to
the phenyl-ring skeleton (Table 3, entry 16; 97% ee, 7:1 d.r.).
The absolute configuration of the products was assigned
based on single-crystal X-ray analysis of 3l (Figure 3).[21]
Scheme 2. Plausible reaction mechanism.
and afforded a stable Knoevenagel product 8a in 99%
yield, probably through a fast elimination process of the
active intermediate 7a [Eq. (8)]. On the basis of the two
controlled experiments above, we believe that, in this case,
the Mannich reaction is faster than the Michael reaction.
Thereby, we conclude that the pathway B (Scheme 2, a Man-
nich–Michael cascade sequence) is a more reasonable mech-
anism than the pathway A (Scheme 2, a Michael–Mannich
cascade sequence).
Figure 3. X-ray crystal structure of 3l.
Aside from the two-component reaction above, a three-
component cascade reaction of 2-alkenyl anline, benzalde-
hyde, and malononitrile was eventually disclosed under ap-
propriate reaction conditions to afford the desired com-
pound 3a in a good yield, but with only a moderate stereo-
selection [Eq. (6)]. Meanwhile, the reaction needed a long
time to support a good yield (36 h, 85% yield).
In summary, we have developed an efficient and conven-
ient cascade process for the synthesis of optically pure tetra-
hydroquinolines in excellent yields (up to 97%) and with
good diastereoselectivities (up to 9.9:1 d.r.) and excellent
enantioselectivities (up to >99% ee). This protocol pro-
ceeds through a Mannich–Michael cascade sequence. We
hope that the catalytic system and strategy demonstrated
here can be applied to other asymmetric transformations to
efficiently assemble further chiral complex structures. The
elaboration of the above synthesized products to other types
of biologically active compounds and further applications of
our indane amine-thiourea catalytic system are now ongoing
in our group.
As shown in Scheme 2, we proposed two plausible catalyt-
ic pathways. The cascade reaction can proceed initially by
a Mannich reaction or a Michael reaction. Which one is the
first option? To answer this question, two control experi-
ments were performed. Chalcone 4 was allowed to react
with malononitrile (2a), but afforded only a trace amount of
the Michael adduct 5a under standard conditions [Eq. (7),
<5% yield, 20 min]. However, the Mannich reaction be-
tween imine 6 and malononitrile (2a) proceeded in 20 min
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Functionalized Tetrahydroquinolines
COMMUNICATION
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General procedure: Malononitrile (2a, 10.2 mg, 0.16 mmol) was added to
a solution of (E)-3-{2-[(E)-benzylideneamino]phenyl}-1-phenylprop-2-en-
1-one (1a, 25.6 mg, 0.08 mmol) in xylenes (0.4 mL) at room temperature,
followed by the addition of catalyst V (2.9 mg, 0.008 mmol). The mixture
was stirred at room temperature for 10 h. The crude product was purified
by column chromatography on silica gel and eluted by hexane/EtOAc=
10:1 to afford the desired product 3a as a white solid (29.7 mg, 97%
yield). 1H NMR (300 MHz, CDCl3): d=7.96 (dd, J=9.8, 8.4 Hz, 2H),
7.73–7.55 (m, 3H), 7.53–7.43 (m, 5H), 7.14 (dd, J=7.3, 5.5 Hz, 2H),
6.82–6.59 (m, 1H), 4.75 (s, 1H), 4.61 (dd, J=6.5, 4.9 Hz, 1H), 4.44 (s,
1H), 3.58 ppm (dd, J=5.7, 2.3 Hz, 2H); 13C NMR (75 MHz, CDCl3): d=
195.1, 140.6, 136.3, 135.5, 133.9, 130.7, 129.9, 129.4, 129.4, 129.0, 128.4,
128.2, 119.7, 117.9, 115.0, 114.0, 113.3, 58.3, 44.9, 42.5, 39.6 ppm; HRMS
(ESI): m/z calcd for C25H20N3O: 378.1601 [M+H]+; found: 378.1599;
HPLC (Chiralpak IC, iPrOH/hexane 10:90, flow rate: 1.0 mLminÀ1, l=
254 nm): tminor =13.8 min, tmajor =18.5 min, ee>99%; [a]25D =À45.0 (c=
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Acknowledgements
The authors acknowledge the National University of Singapore and Min-
istry of Education (Singapore) for financial support (Academic Research
Grant:
R143000480112).
R143000408133,
R143000408733,
R143000443112,
and
Keywords: asymmetric synthesis
· cascade reactions ·
organocatalysis · tetrahydroquinolines · thioureas
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Received: October 5, 2011
Published online: February 29, 2012
3870
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ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2012, 18, 3865 – 3870