Organocatalytic asymmetric three-component cyclization of cinnamaldehydes and primary amines with 1,3-dicarbonyl compounds: Straight forward access to enantiomerically enriched dihydropyridines

Article abstract of DOI:10.1002/anie.200705300

(Chemical Presented) All in together: The title reaction takes place under mild conditions in the presence of a chiral phosphonic acid catalyst to provide 4-aryl substituted 1,4-dihydropyridines with up to 98% ee (see scheme). The products are useful substrates for the asymmetric synthesis of tetrahydropyridines and multifunctional piperidines, which are common substructures of natural products and pharmaceuticals. R¹=aryl; R²,R³ = alkyl.

Full text of DOI:10.1002/anie.200705300

Communications
DOI: 10.1002/anie.200705300
Multicomponent Reactions
Organocatalytic Asymmetric Three-Component Cyclization of
Cinnamaldehydes and Primary Amines with 1,3-Dicarbonyl
Compounds:Straightforward Access to Enantiomerically Enriched
Dihydropyridines**
Jun Jiang, Jie Yu, Xi-Xi Sun, Qin-Quan Rao, and Liu-Zhu Gong*
Dihydropyridines (DHPs), in particular 4-aryl-substituted
1,4-dihydropyridines, have been recognized as an important
class of organic calcium-channel modulators for the treatment
of cardiovascular diseases[1] since the first description of the
pharmacology of these compounds by Loev et al.[2] Structural
modification led to a large family of compounds containing
the 1,4-dihydropyridine moiety. In a series of biological
assays, these compounds were found to have a broad range of
other pharmaceutical activities.[3] The absolute configuration
of the stereogenic center of chiral DHPs has considerable
influence on their biological activity.[4] The application of
chiral dihydropyridines in the synthesis of alkaloids has been
reported,[5] and the use of optically pure C4-substituted 1,4-
dihydropyridines as chiral models of NAD(P)H has also
received much attention.[6] Therefore, efficient methods for
the synthesis of optically active 1,4-dihydropyridines would
be of great value for drug discovery and organic synthesis.
Until now, however, optically active DHPs could only be
accessed by asymmetric synthesis with chiral auxiliaries and
by resolution.[4a,5] Despite the large number of procedures
that yield DHPs,[7,8] a catalytic asymmetric synthesis of highly
enantiomerically enriched 4-aryl-substituted 1,4-dihydropyr-
idines has not appeared, and thus remains an important
challenge. Herein, we report an asymmetric three-component
cyclization of an a,b-unsaturated aldehyde 1, a primary amine
2, and an acetoacetate 3 in the presence of a chiral Brønsted
acid as a catalyst to give chiral 1,4-dihydropyridines 4[8] with
excellent enantioselectivities of up to 98% ee [Eq. (1)].
Our initial proposal for the Brønsted acid catalyzed
cyclization reaction of an a,b-unsaturated aldehyde 1, a
primary amine 2, and an acetoacetate 3 is outlined in
Scheme 1. Under acidic conditions, a,b-unsaturated alde-
Scheme 1. Proposed mechanism for the cyclization reaction of a,b-
unsaturated aldehydes and primary amines with 1,3-dicarbonyl com-
pounds under the catalysis of a chiral Brønsted acid.
[*] J. Yu, X.-X. Sun, Q.-Q. Rao, Prof. L.-Z. Gong
Hefei National Laboratory for Physical Sciences at the Microscale
and
hydes 1 condense with primary amines 2 to form a,b-
unsaturated imines 5 with a 1-aza-1,3-butadiene structure,
and acetoacetates 3 enolize into their tautomers 6, which are
nucleophiles. The chiral Brønsted acid (BH*) makes imines 5
more electron deficient by forming a hydrogen bond with the
N atom and thereby promotes the Michael addition of 6 to 5
via a possible transition state I. The resulting intermediate II
undergoes cyclization to give III.[9,10] Finally, intermediate III
undergoes a dehydration reaction to afford optically active
dihydropyridines 4.
Department of Chemistry
University of Science and Technology of China
Hefei, 230026 (China)
Fax: (+86)551-360-6266
E-mail: gonglz@ustc.edu.cn
J. Jiang, Prof. L.-Z. Gong
Chengdu Institute of Organic Chemistry
Chinese Academy of Sciences (CAS)
Chengdu, 610041 (China)
Recently, chiral phosphonic acids have been recognized as
efficient catalysts for asymmetric nucleophilic addition to
imines.[11,12] In particular, we have demonstrated that these
chiral Brønsted acids can catalyze some important multi-
component reactions with high enantioselectivity.[13]
Although chiral phosphonic acids had not been used to
activate 1-aza-1,3-butadienes for cycloaddition reactions,
J. Jiang
Graduate School of the Chinese Academy of Sciences
Beijing (China)
[**] We are grateful for financial support from NSFC (20732006 and
20325211) and CAS.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Chemie
these previous successes led us to believe that 7 and 8 may
promote enantioselective cyclization reactions of a,b-unsatu-
to enhanced enantioselectivity (Table 1, entries 2–5). Thus, 7d
and 8, which afforded 4a in fairly good yields and enantio-
selectivities (Table 1, entries 4 and 5), were found to be the
most promising catalysts for the reaction. Optimization of the
reaction conditions indicated that an increase in the reaction
temperature led to higher enantioselectivity (Table 1,
entries 6–8). We tested various solvents and observed the
highest enantioselectivity when the reaction was carried out
in PhCN. Thus, 4a was formed in the presence of the
phosphonic acids 7d and 8 in PhCN at 508C with 89 and
90% ee, respectively (Table 1, entries 9–10). The enantiose-
lectivity could be improved to 92% ee by using 10 mol% of 8
(Table 1, entry 11).
Next, we explored the scope of the reaction with respect
to the aniline component by using p-nitrocinnamaldehyde
and ethyl acetoacetate as the other two reactants. Both the
reaction efficiency and the enantioselectivity were found to
depend significantly on the substituent on the aromatic ring
(Table 2). The reaction in which p-anisidine was used as the
rated aldehydes 1 with primary amines 2 and acetoacetates 3
via the proposed key transition structures IVand V (Figure 1)
to generate optically active DHPs 4 through a reaction
sequence similar to that shown in Scheme 1.
Table 2: Cyclization reaction of p-nitrocinnamaldehyde and ethyl acetoa-
cetate with different primary amines.[a]
Figure 1. The proposed key transition structures for the phosphonic
acid-catalyzed cyclization reaction of a,b-unsaturated aldehydes and
amine with 1,3-dicarbonyls.
The initially tested three-component cyclization reaction
of p-nitrocinnamaldehyde (1a) and p-anisidine (2) with ethyl
acetoacetate (3a) proceeded smoothly in the presence of the
chiral phosphonic acid 7a (20 mol%) in chloroform at room
temperature to furnish the desired product 4a in 72% yield,
albeit with just 19% ee (Table 1, entry 1). The screening of
phosphonic acids 7b–d and 8 revealed that an increase in the
size of the substituents at the 3,3’-positions of the catalyst led
Entry
R2 (2)
4
Yield [%][b]
ee [%][c]
1
2
3
4
5
4-MeOC6H4 (2a)
3-MeOC6H4 (2b)
4-CH3C6H4 (2c)
3-MeC6H4 (2d)
4-ClC6H4 (2e)
4a
4b
4c
4d
4e
82
53
57
53
60
92
97
96
90
89
[a] Reaction conditions: 1a (0.3 mmol), 2 (0.2 mmol), 3a (0.4 mmol), 8
(0.02 mmol), PhCN (1.5 mL). [b] Yield of the isolated product. [c] The
ee value was determined by HPLC.
Table 1: Catalyst screening and optimization of the reaction conditions.[a]
primary amine component furnished the desired heterocycle
in high yield with excellent enantioselectivity (Table 2,
entry 1). The best enantioselectivity of 97% ee was observed
for the reaction of m-anisidine, although the yield of the
product was comparatively low (Table 2, entry 2). In contrast
to the trend observed with the anisidine substrates, the
reaction of p-toluidine proceeded with higher enantioselec-
tivity than that of m-toluidine (96 versus 90% ee; Table 2,
entries 3 and 4). Even lower enantioselectivity was observed
for the reaction of 4-chloroaniline (Table 2, entry 5). Thus, an
electron-withdrawing substituent on the aniline appears to
have a negative effect on the stereoselectivity of the cycliza-
tion.
We then investigated the generality of the protocol with
respect to the other two substrates, the b-ketoester 3 and the
a,b-unsaturated aldehyde 1 (Table 3). A range of b-ketoesters
was first examined in the reaction with p-nitrocinnamalde-
hyde (1a) and p-anisidine (2a; Table 3, entries 1–4). The
enantioselectivity was highly dependent on the size of the
ester moiety. Thus, cyclization reactions with ethyl and
isopropyl acetoacetate provided the product with 92% ee
Entry
Catalyst
Solvent
T [8C]
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
9
7a
7b
7c
7d
8
7d
7d
8
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
PhCN
PhCN
PhCN
25
25
25
25
25
40
50
50
50
50
50
72
85
62
67
69
80
85
86
82
83
82
19
19
31
73
64[d]
80
82
72[d]
89
7d
8
8
10
90[d]
92[d]
11[e]
[a] A solution of 1a (0.3 mmol), 2a (0.2 mmol), 3a (0.4 mmol), and the
indicated catalyst in CHCl3 or PhCN (1.5 mL) was stirred for 36 h.
[b] Yield of the isolated product. [c] The ee value was determined by
HPLC; (S)-4a was obtained unless otherwise indicated. [d] The product
was (R)-4a. [e] The reaction was carried out with 10 mol% of 8. PMP=p-
methoxyphenyl.
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Table 3: Cyclization reaction of cinnamaldehydes and p-or m-anisidine
with 1,3-dicarbonyl compounds.[a]
cyclization reactions of ortho-substituted cinnamaldehydes
and acetylacetates with 2a or 2b proceeded with high
enantioselectivities (82–97% ee; Table 3, entries 14–22),
which were highly dependent on the substituents of the
three reaction components. The reaction of a b-alkyl-sub-
stituted unsaturated aldehyde led to the product in low yield
with 66% ee (Table 3, entry 23).
Further studies on the cyclization reaction of acetylace-
tone and p- or m-anisidine (2a,b) with various cinnamalde-
hydes revealed that the use of acetylacetone as a reaction
component led to lower enantioselectivities than those
observed with the structurally analogous acetoacetates.
Accordingly, the dihydropyridines 9 were furnished in
moderate yields with good ee values (73–88% ee; Table 4).
Entry R1
2
R2
R3
4
Yield [%][b] ee [%][c]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23[d]
4-NO2C6H4
2a Me Et
2a Me iPr
2a Me allyl 4g
2a Me Me
2b Me Et
2b Me iPr
2b Me allyl 4j
2b Me Me
2a Et Me
2a Me iPr
2a Me Et
2b Me Et
2a Me Et
2a Me Et
2b Me Et
2a Me Me
2b Me Me
4a
4 f
82
81
75
93
53
48
52
47
38
92
92
82
81
97
95
95
91
91
81
87
96
91
94
98
88
96
82
94
97
96
93
66
4-NO2C6H4
4-NO2C6H4
4-NO2C6H4
4-NO2C6H4
4-NO2C6H4
4-NO2C6H4
4-NO2C6H4
4-NO2C6H4
Ph
2,3-Cl2C6H3
2,3-Cl2C6H3
3-NO2C6H4
2-NO2C6H4
2-NO2C6H4
2-NO2C6H4
2-NO2C6H4
4h
4b
4i
4k
4l
4m 40
4n
4o
4p
4q
4r
Table 4: Cyclization reaction of cinnamaldehydes and acetylacetone with
primary amines.[a]
72
72
70
72
37
85
53
50
74
69
75
70
31
Entry
9
R1
R2
Yield [%][b]
ee [%][c]
4s
4t
1
2
3
4
5
6
7
9a
9b
9c
9d
9e
9 f
9g
4-NO2C6H4
2-NO2C6H4
2-BrC6H4
2,3-Cl2C6H3
3-NO2C6H4
3-NO2C6H4
2-CF3C6H4
PMP
PMP
PMP
PMP
PMP
3-MeOC6H4
3-MeOC6H4
60
69
63
72
64
52
48
81
88
73
77
79
87
86
2-MeOC6H4 2a Me iPr
4u
4v
4w
4x
4y
4z
2-ClC6H4
2-ClC6H4
2-CF3C6H4
2-BrC6H4
nPr
2a Me Et
2b Me Et
2a Me Et
2a Me Et
2a Me Et
[a] A solution of 1 (0.3 mmol), 2a or 2b (0.2 mmol), 3c (0.4 mmol), and
8 (0.02 mmol) in PhCN (1.5 mL) was stirred at 508C for 24 h. [b] Yield of
the isolated product. [c] The ee value was determined by HPLC.
[a] A solution of 1 (0.3 mmol), 2a or 2b (0.2 mmol), 3 (0.4 mmol), and 8
(0.02 mmol) in PhCN (1.5 mL) was stirred at 508C for 24 h. [b] Yield of
the isolated product. [c] The ee value was determined by HPLC. [d] The
reaction was carried out with 20 mol% of 8 and 4-Š molecular sieves
(100 mg). The reaction mixture was stirred at 608C for 48 h.
The highly enantiomerically enriched dihydropyridines
obtained by this method are multifunctional compounds that
can be converted into other optically active heterocycles by
conventional reactions. For example, upon the treatment of
4a with 10 in the presence of triethylamine, a 1,3-dipolar
addition[14] occurred to give the heterocycle 11 in 67% yield
with 96% ee (Scheme 2).
The reduction of 4a with trimethylsilane in the presence
of trifluoroacetic acid (TFA) produced the tetrahydropyri-
dine 12 in 85% yield (Scheme 3).[15] Compound 12 was
reduced further with NaBH4 in acetic acid to give the
trisubstituted piperidine 13 in 76% yield with the same
ee value; no other diastereomers were observed.[16] Chiral
tetrahydropyridines and multisubstituted piperidines are
(Table 3, entries 1 and 2). However, much lower enantiose-
lectivities were observed for methyl and allyl acetoacetate
(Table 3, entries 3 and 4). The equivalent reactions with m-
anisidine in place of p-anisidine as a reaction component
proceeded with considerably higher enantioselectivities (91–
97% ee), although the products were formed in lower yields
(Table 3, entries 5–8). Methyl propionylacetate was found to
be less reactive than the acetoacetates and underwent
cyclization with 1a and 2a to give the corresponding product
in lower yield; however, high enantioselectivity was observed
(91% ee; Table 3, entry 9).
Next, various a,b-unsaturated aldehydes were examined
as substrates for the cyclization reaction. The substituent on
the aromatic ring of the cinnamaldehyde had a dramatic
effect on the stereoselectivity. Cinnamaldehyde itself under-
went the cyclization reaction to furnish the desired product
with fairly good enantioselectivity (Table 3, entry 10). The
reaction of 2,3-dichlorocinnamaldehyde, 2a, and ethyl ace-
toacetate delivered the dihydropyridine 4n in 72% yield with
87% ee (Table 3, entry 11). The desired product was formed
with much higher enantioselectivity (96% ee) in the reaction
of the same aldehyde and 1,3-dicarbonyl compound with 2b
(Table 3, entry 12). High enantioselectivity was observed with
m-nitrocinnamaldehyde (91% ee; Table 3, entry 13). The
Scheme 2. Application of a dihydropyridine in the synthesis of another
optically active heterocycle.
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ces the importance of this asymmetric cyclization reaction.
This study also indicates that the application of Brønsted
acids, in particular chiral phosphonic acids, might be extended
to the promotion of other asymmetric addition reactions of
suitable nucleophiles to 1-aza-1,3-butadienes.
Experimental Section
Scheme 3. Application of a dihydropyridine in the synthesis of a
General Procedure: A solution of the aldehyde (0.3 mmol), the
primary amine (0.2 mmol), and the chiral phosphonic acid
(0.02 mmol) in PhCN (1.5 mL) was stirred at 258C for 15 min. The
b-dicarbonyl compound (0.4 mmol) was then added, and the resulting
mixture was stirred at 508C for 1 day. (The reaction was monitored by
TLC.) Flash column chromatography of the reaction mixture on silica
gel (eluent: petroleum ether/ethyl acetate 50:1) yielded the pure
product.
tetrahydropyridine and a piperidine.
important synthetic intermediates and common substructures
found in biologically active natural products and synthetic
pharmaceuticals.[17,18] Thus, the chiral DHPs formed in the
three-component cyclization are of broad importance.
The absolute configuration of 4a was assigned by X-ray
crystallographic analysis of compound 14 (Figure 2), which
Received: November 19, 2007
Revised: December 18, 2007
Published online: February 21, 2008
Keywords: asymmetric catalysis · cyclization · dihydropyridines ·
.
multicomponent reactions · organocatalysis
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cyclization reaction between a cinnamaldehyde, an aromatic
primary amine, and a 1,3-dicarbonyl compound enables the
straightforward synthesis of enantiomerically enriched 4-aryl-
substituted 1,4-dihydropyridines with high enantioselectivity
(up to 98% ee). The application of the resulting DHPs in the
synthesis of optically active heterocyclic compounds through
1,3-dipolar addition and diastereoselective reduction enhan-
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