Organocatalytic asymmetric multicomponent reactions of aromatic aldehydes and anilines with β-ketoesters: Facile and atom-economical access to chiral tetrahydropyridines

Article abstract of DOI:10.1039/c2cc38349g

The first catalytic asymmetric pseudo five-component (AB₂C ₂ type) reaction is reported. A spirocyclic chiral phosphoric acid catalyzed one-pot multicomponent reaction of aromatic aldehydes, anilines and β-ketoesters and afforded highly functionalized enantioenriched tetrahydropyridines with high levels of stereocontrol.

Full text of DOI:10.1039/c2cc38349g

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Organocatalytic asymmetric multicomponent reactions
of aromatic aldehydes and anilines with b-ketoesters:
facile and atom-economical access to chiral
tetrahydropyridines†
Cite this: DOI: 10.1039/c2cc38349g
Received 20th November 2012,
Accepted 21st December 2012
DOI: 10.1039/c2cc38349g
Xuejian Li, Yanyan Zhao, Haijun Qu, Zhenjun Mao and Xufeng Lin*
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The first catalytic asymmetric pseudo five-component (AB2C2 type) 1,10-spirobiindane-7,70-diol, which effectively catalyzed the
reaction is reported. A spirocyclic chiral phosphoric acid catalyzed highly enantioselective Friedel–Crafts reaction, Pictet–Spengler
one-pot multicomponent reaction of aromatic aldehydes, anilines reaction, Biginelli reaction and Povarov reaction.7 List, Hu and
and b-ketoesters and afforded highly functionalized enantio- Zhou also independently reported that SPINOL-phosphoric
enriched tetrahydropyridines with high levels of stereocontrol.
acids could afford higher enantioselectivity than BINOL-derived
counterparts in some cases.8 These previous successes led us to
Asymmetric multicomponent reactions (AMCRs) have emerged envision that SPINOL-phosphoric acids would effectively
as a powerful strategy in organic and medicinal chemistry as catalyze the enantioselective multicomponent reaction of
they are facile, efficient and have a high degree of atom aromatic aldehydes 1, anilines 2 and b-ketoesters 3 to generate
economy.1 These features make AMCRs well suited for the easy enantioenriched tetrahydropyridines 4.
construction of diversified chiral heterocyclic scaffolds from
Our initial proposal for the SPINOL-phosphoric acid catalyzed
readily available starting materials.2 The functionalized tetra- multicomponent reaction is shown in Scheme 1. Under acidic
hydropyridine ring systems represent an important class of conditions, aromatic amine 2 condenses with b-ketoester 3 to
heterocycles in organic chemistry.3 In recent times, many form enamine A, which may react with aromatic aldehyde 1 to
methods have been reported describing the one-pot, pseudo give the Knoevenagel-type product B. Then, tautomerisation of
five-component (AB2C2) synthesis of highly functionalized imine to the enamine produces a diene C. Another equivalent
tetrahydropyridines, based on various catalysts from the of amine and aldehyde react to generate the corresponding
multicomponent reaction of b-ketoesters, aldehydes and imine D. Sequentially, a possible transition state E is formed via
amines.4 However, development of a catalytic enantioselective protonation of the imine D with a SPINOL-phosphoric acid
multicomponent variant, which allows the rapid construction catalyst, followed by hydrogen-bonding between the enamine
of optically active tetrahydropyridines, remains an elusive NH of C and Lewis basic phosphoryl oxygen. A pseudo-intra-
problem. We now report the recently introduced chiral molecular 1,2-addition reaction of the chiral contact ion pairs
SPINOL-derived phosphoric acid catalyzed, one-pot, enantio- via transition state E would then give iminium F.9 The resulting
selective MCR of aromatic aldehydes 1, anilines 2 and intermediate
F undergoes an intramolecular 1,4-addition
b-ketoesters 3 to obtain enantioenriched tetrahydropyridines reaction to afford G. Finally, intermediate G tautomerizes to
4 with high levels of stereocontrol.
provide optically active tetrahydropyridines 4.
Over the past decade, as an environmentally benign and
In our initial study, we examined the pseudo five-component
practical methodology for asymmetric synthesis, enantio- model reaction between two equivalents of aromatic aldehyde 1a,
selective organocatalysis has been hotly pursued.5 Chiral
cyclic phosphoric acids have been recognized as efficient
organocatalysts for a variety of enantioselective transforma-
tions.6 Recently, our group has developed a novel class of
spirocyclic SPINOL-phosphoric acids derived from chiral
Department of Chemistry, Zhejiang University, Hangzhou 310027, P. R. China.
E-mail: lxfok@zju.edu.cn
† Electronic supplementary information (ESI) available. CCDC 885330 and
898709. For ESI and crystallographic data in CIF or other electronic format see
Scheme 1 Proposed chiral SPINOL-phosphoric acid-catalyzed AMCR.
DOI: 10.1039/c2cc38349g
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Table 1 Optimization of reaction conditionsa
Table 2 Scope of the reactiona
4a, 65%
4b, 52%
4c, 40%
>20 : 1 dr, >99% ee
16 : 1 dr, 90% ee
10 : 1 dr, 85% ee
Entry Catalyst Solvent
T (1C) Yieldb (%) drc
eed (%)
1
2
3
4
5
6
5a
5a
5a
5a
5a
5a
5a
5a
5a
5a
5b
5c
5d
6a
6b
6c
6b
ClCH2CH2Cl rt
79
92
15
71
87
82
76
81
72
65
5
5.1 : 1
3.2 : 1
4 : 1
73
33
63
72
81
86
89
84
93
CH2Cl2
CH3CN
Xylene
rt
rt
rt
rt
4d, 53%
4e, 48%b
4f, 60%c
6.8 : 1
2.5 : 1
3.7 : 1
4.2 : 1
2.1 : 1
13.6 : 1
>20 : 1
2.7 : 1
5 : 1 dr, 75% ee
5 : 1 dr, 88% ee
>20 : 1 dr, 40% ee
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
ꢀ15
ꢀ30
ꢀ30
ꢀ30
ꢀ30
ꢀ30
ꢀ30
ꢀ30
ꢀ30
ꢀ30
ꢀ30
50
7
8e
9f
10g
11
12
13
14
15
16
17
>99
>99
25
Trace
40
0
1 : 1.7 >99
—
—
87
—
—
20
3.6 : 1
—
—
4g, 39%
4h, 47%
4i, 54%
5 : 1 dr, 97% ee
>20 : 1 dr, 90% ee
8 : 1 dr, 92% ee
0
65
10 : 1
a
Reaction conditions: catalyst (10 mol%, 0.01 mmol), 1a (0.2 mmol), 2a
b
(0.2 mmol), 3a (0.1 mmol), MS 4 Å (0.1 g), solvent (1 mL), 3 days. Yield
of the isolated isomers. dr = trans/cis; determined by 1H NMR analysis
c
d
e
of the crude product. Determined by chiral HPLC analysis. Solvent
(0.5 mL). Solvent (2 mL). Solvent (3 mL).
4j, 45%
8 : 1 dr, >99% ee
4k, 55%
10 : 1 dr, 96% ee
4l, 49%
f
g
>20 : 1 dr, 91% ee
(>99% ee)d
a
Reaction conditions: 5a (10 mol%, 0.01 mmol), 1 (0.2 mmol), 2
(0.2 mmol), 3 (0.1 mmol), MS 4 Å (0.1 g), toluene (3 mL), ꢀ30 1C,
3 days. Yields given are for the isolated trans isomer. Diastereomeric
ratios (dr = trans/cis) were determined by 1H NMR. ees of the major
two equivalents of amine 2a, and one equivalent b-ketoester 3a.
Indeed, the reaction proceeded using a 10 mol% chiral phos-
phoric acid catalyst in the presence of powdered 4 Å molecular
sieves to afford the desired optically active tetrahydropyridine
4a, as summarized in Table 1. Screening of the solvent effect
revealed that all the reactions proceeded smoothly to give
the desired product 4a in good yields, except acetonitrile, with
10 mol% chiral SPINOL-phosphonic acid 5a at room tempera-
ture (entries 1–5). Toluene proved to be a promising solvent,
affording product 4a with 81% ee (entry 5). Lowering the
temperature to ꢀ15 1C or ꢀ30 1C slightly improved the
diastereo- and enantioselectivity of the reaction (entries 6 and 7).
It is notable that a subsequent concentration survey revealed that
concentration remarkably changed the diastereo- and enantio-
selectivity (entries 7–10). Low concentration further improved
the diastereoselectivity to >20 : 1 and enantioselectivity to
>99% (entry 10). We also tested other chiral phosphoric acids.
Interestingly, the screening of SPINOL-phosphonic acids 5a–d
revealed that the 6,60-substituents on the SPINOL backbone
remarkably effected the catalytic activity and diastereoselectivity,
while excellent enantioselectivity (>99% ee) was provided by all
except 5d (entries 10–13). Of BINOL-phosphoric acids 6, catalyst
6a gave the desired product in 40% yield with 3.6 : 1 dr and 87%
ee, whereas no catalytic activity was observed with 6b and 6c in
b
c
diastereomers were determined by chiral HPLC. At ꢀ15 1C. At 35 1C
d
with 20 mol% 5a. Data in parentheses were obtained after single
recrystallization.
this model reaction under the current conditions (entries 14–16).
When the model reaction was carried out at 50 1C using catalyst
6b, the catalytic activity could be improved, but affording only
20% ee (entry 17). Thus, the most suitable reaction conditions
for the model reaction were established (entry 10).
With these reaction conditions identified, our attention
turned to examination of the scope of the multicomponent
reaction between aromatic aldehydes 1, anilines
2 and
b-ketoesters 3 (Table 2). The substituent on the aromatic ring
of the aldehyde had a dramatic effect on the activity and
stereoselectivity. The reactions involving the electron-withdraw-
ing aldehydes proceeded smoothly in moderate yields with
good diastereoselectivities (up to >20 : 1 dr) in favor of the
trans isomer, which delivered the corresponding products
4a–4d with good to excellent enantioselectivities (up to >99% ee).
Benzaldehyde could deliver product 4e with 5 : 1 dr and 88% ee.
An electron-rich substituent on the aromatic aldehyde appears to
have a remarkably negative effect on the reaction activity.
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excellent stereocontrol, atom economy, and the products are valu-
able for the synthetic application to optically active piperidines.
We thank National Natural Foundation of China (21272202)
and Fundamental Research Funds for the Central Universities.
Notes and references
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Scheme 2 Synthesis of tetrahydropyridine 4m.
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Scheme 3 Synthesis of chiral piperidine.
Throughout our studies, the multicomponent reaction involving
an electron-rich substrate did not occur under the standard
optimized reaction conditions, whereas by increasing the
temperature to 35 1C and the catalyst loading to 20 mol%, the
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tetrahydropyridine 4f, which was obtained in 60% yield with
>20 : 1 dr and only 40% ee. Pleasingly, a bromo-substituent on
the aniline, which can participate in subsequent transforma-
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desired products 4j–4l with good diastereoselectivities (8 : 1 -
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excellent diastereo- and enantioselectivity (17 : 1 dr and 91% ee)
(Scheme 2).
As a further demonstration of the utility of this current
protocol, the reduction of 4e produced the enantiomerically
enriched piperidine 7 in 67% yield of the major isomer with
maintained enantioselectivity (Scheme 3). The absolute
configuration of product 7 was assigned as (2S,3R,4S,6S).10
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this organocatalytic asymmetric multicomponent reaction provides 10 CCDC 885330 and 898709†.
c
This journal is The Royal Society of Chemistry 2013
Chem. Commun.