Catalytic asymmetric five-component tandem reaction: Diastereo- and enantioselective synthesis of densely functionalized tetrahydropyridines with biological importance

Article abstract of DOI:10.1002/adsc.201300001

The first catalytic asymmetric five-component tandem reactions of β-keto esters, aromatic aldehydes and anilines have been established in the presence of a chiral phosphoric acid, affording densely functionalized tetrahydropyridines with concomitant gener

Full text of DOI:10.1002/adsc.201300001

FULL PAPERS
DOI: 10.1002/adsc.201300001
Catalytic Asymmetric Five-Component Tandem Reaction:
Diastereo- and Enantioselective Synthesis of Densely
Functionalized Tetrahydropyridines with Biological Importance
Feng Shi,a,* Wei Tan,a Ren-Yi Zhu,a Gui-Juan Xing,a and Shu-Jiang Tua,*
a
School of Chemistry & Chemical Engineering, and Jiangsu Key Laboratory of Green Synthetic Chemistry for Functional
Materials, Jiangsu Normal University, Xuzhou, 221116, Peopleꢀs Republic of China
E-mail: fshi@jsnu.edu.cn or laotu@jsnu.edu.cn
Received: January 1, 2013; Revised: April 29, 2013; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300001.
Abstract: The first catalytic asymmetric five-compo- situ generated imine, which supported the proposed
nent tandem reactions of b-keto esters, aromatic al- tandem [4+2] reaction pathway to some extent. This
dehydes and anilines have been established in the protocol not only represents the first enantioselective
presence of a chiral phosphoric acid, affording example of this five-component tandem reaction, but
densely functionalized tetrahydropyridines with con- also provides an unprecedented access to enantioen-
comitant generation of five s bonds and two stereo- riched tetrahydropyridines with structural diversity,
genic centers in high diastereo- and enantioselectivi- which holds great potential in medicinal chemistry.
ties (up to >99:1 dr, 95:5 er). In addition, the first
isolation and preparation of a diene species as the
key intermediate of the reaction has been successful- Keywords: asymmetric catalysis; chirality; densely
ly realized, leading to the formation of the desired functionalized tetrahydropyridines; enantioselectivi-
tetrahydropyridine via further condensation with in ty; multicomponent reactions; organic catalysis
Introduction
1,2,5,6-Tetrahydropyridines and piperidines are im-
portant heterocycles,[6] which constitute the core
The past decades have witnessed the great success of structures of a variety of natural products and phar-
multicomponent reactions (MCRs) as
a
robust maceuticals (Figure 1).[7] In addition, recent studies
method to create molecules with structural diversity have revealed that densely functionalized 1,2,5,6-tet-
and complexity.[1] The tremendous advantages of rahydropyridines (compounds I and II, in Figure 1)
MCRs[2] have made this protocol quite closely ap-
proach the realization of the ideal synthesis.[3] On the
other hand, the increasing number of applications of
optically pure compounds in the pharmaceutical in-
dustry has created a great demand for the develop-
ment of asymmetric multicomponent reactions
(AMCRs),[4] especially catalytic enantioselective
MCRs, which assemble three or more achiral reagents
in a single step to form two or more bonds and at
least one stereogenic center in the presence of
a chiral catalyst.[5] However, in sharp contrast to well-
established non-enantioselective MCRs, the catalytic
enantioselective MCR is still in its infancy.[1b,4c] There-
fore, the development of catalytic asymmetric ver-
sions of existing MCRs has become a formidable chal-
lenge for the synthesis of optically pure compounds
with structural diversity and complexity.
Figure 1. 1,2,5,6-Tetrahydropyridine and piperidine-related
natural products and pharmaceuticals.
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exhibit potent antimalarial[8] and anticancer[9] activi- to further reaction, which strongly supported the pro-
ties. posed tandem [4+2] reaction pathway.
As a result, extensive attention has been paid to
the synthesis of this series of heterocycles, and some
developments have been achieved in the non-enantio- Results and Discussion
selective MCRs which afford the racemic 1,2,5,6-tet-
rahydropyridines [Eq. (1)].[8–10] However, in contrast, Our study commenced with a five-component reac-
no catalytic enantioselective versions of this MCR tion of two equivalents of 4-methoxyaniline 1a,
have been established in spite of the great demand methyl acetoacetate 2a and two equivalents of 4-bro-
for optically pure 1,2,5,6-tetrahydropyridines [Eq. mobenzaldehyde 3a in the presence of 10 mol% of
(2)]. Thus, the development of this type of catalytic chiral phosphoric acids (CPAs) 4 in toluene at 358C
enantioselective MCR is highly desirable.
(Table 1). The initial results revealed that CPAs 4a–4e
We have recently established a series of chiral with bulky groups at the 3,3’-positions of the BINOL
phosphoric acid-catalyzed[11] MCRs for the prepara- backbone had inferior catalytic activity (entries 1–5),
tion of enantioenriched heterocycles with potential while CPA 4f with 3,3’-p-chlorophenyl groups was
bioactivities.[12] Inspired by these successes and in much superior to other analogues, affording the de-
view of the fact that there is so far no enantioselective sired tetrahydropyridine 5aaa in 56% yield, 80:20 dr
version of this five-component reaction together the and 91:9 er (entry 6). Subsequent changing in the
importance of densely functionalized tetrahydropyri- para-substituents of 3,3’-phenyl rings (entries 7–10)
dines, we decided to employ a chiral phosphoric acid led to the finding that electron-donating substituents
to catalyze this five-component reaction, wherein the would decrease the yield and enantioselectivity (en-
nitrogen-containing intermediates should be activated tries 7 and 8), while electron-withdrawing ones would
by this type of catalyst via hydrogen-bonding interac- increase the yield but still with reduced enantioselec-
tions (Scheme 1).
tivity (entries 9 and 10). Furthermore, there was no
Herein, we report the first catalytic asymmetric evident steric effect among these substituents and no
five-component reaction, which directly assembles al- other tested CPAs could deliver a higher er value
dehydes, anilines and b-keto esters into densely func- than 4f. Then, the model reaction in the presence of
tionalized tetrahydropyridines with concomitant gen- 4f was performed in a wide range of solvents to find
eration of five s bonds and two stereogenic centers in the optimal reaction medium. Several halogen-substi-
high diastereo- and enantioselectivities (up to 99:1 dr, tuted benzenes were tentatively employed as solvents
95:5 er). Besides, the key intermediate of the reaction (entries 11–13), and bromobenzene afforded the prod-
has been firstly isolated or synthesized and subjected uct in the highest yield of 73% but with inferior enan-
Scheme 1. The designed activation mode of chiral catalyst to the intermediates.
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Catalytic Asymmetric Five-Component Tandem Reaction
Table 1. The screening of catalysts and solvents.[a]
Entry
4
Solvent
Yield [%][b]
dr[c] (trans:cis)
er[d]
1[e]
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19[e]
4a
4b
4c
4d
4e
4f
4g
4h
4i
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
FPh
ClPh
BrPh
CH2Cl2
CHCl3
CCl4
–
–
–
34
47
19
56
56
35
48
67
68
67
64
73
59
69
61
16
47
–
89:11
87:13
76:24
71:29
80:20
76:24
73:27
80:20
84:16
80:20
75:25
83:17
67:33
67:33
67:33
86:14
92:8
61:39
77:23
78:22
80:20
91:9
86:14
16:84
15:85
13:87
89:11
86:14
85:15
87:13
89:11
88:12
92:8
4j
4f
4f
4f
4f
4f
4f
4f
4f
4f
THF
1,4-dioxane
CH3CN
93:7
–
–
[a]
Unless indicated otherwise, the reaction was carried out on a 0.1-mmol scale in solvent (1 mL) with 3ꢂ MS (100 mg) for
48 h, and the ratio of 1a:2a:3a was 2:1:2.
Isolated yield.
The diatereomeric ratio (dr) was determined by H NMR.
The enantiomeric ratio (er) value refers to the major trans-diastereomer and was determined by HPLC.
[b]
[c]
[d]
[e]
1
No reaction.
tioselectivity (entry 13). Further utilization of chlor- Thus, 1,4-dioxane was finally selected as the solvent
ine-containing alkanes as solvents revealed that there of choice for further investigation.
was no significant difference among them and none of
Subsequently, other reaction parameters such as
them provided a higher er value than toluene (en- molecular sieves (MS), temperature and reagent
tries 14–16). At last, ethers and acetonitrile were ap- ratios were examined in the model reaction (Table 2).
plied to the reaction (entries 17–19), which disclosed In the absence of MS, the reaction proceeded slug-
that 1,4-dioxane was the best solvent by offering the gishly in a low yield and poor diastereoselectivity
highest er value of 93:7 albeit with an unsatisfactory (entry 2 vs. entries 1 and 3), which indicated that MS
yield (entry 18). Surprisingly, acetonitrile as a polar played an important role both in reactivity and in ste-
non-protic solvent failed to facilitate the reaction reoselectivity. 3ꢂ MS exhibited a slight superiority
under the current reaction conditions (entry 19), over 4ꢂ MS in controlling the reactivity and the ste-
which was very different from its efficient perfor- reoselectivity (entry 1 vs. entry 3). Lowering or raising
mance in non-enantioselective tranformations.[8,10a–g,j] the reaction temperature could not improve the er
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Table 2. Further screening of other reaction parameters.[a]
Entry
1a:2a:3a
Yield [%][b]
dr[c] (trans:cis)
er[d]
1
2:1:2
2:1:2
2:1:2
2:1:2
47
23
46
21
39
43
22
42
19
42
59
73
92:8
93:7
89:11
92:8
93:7
92:8
93:7
95:5
93:7
95:5
95:5
93:7
88:12
2[e]
3[f]
4[g]
5[h]
6
50:50
90:10
67:33
92:8
89:11
80:20
88:12
67:33
92:8
2:1:2
2:1:2.4
2:2.5:2
2:1.5:2.4
7.8:6:2
3.5:1:3.5
3.5:1:3.5
2:1:2
7
8
9
10
11[i]
12[j]
90:10
88:12
[a]
Unless indicated otherwise, the reaction was carried out on a 0.1-mmol scale in 1,4-dioxane (1 mL) with 3ꢂ MS (100 mg)
for 48 h.
Isolated yield.
[b]
[c]
[d]
[e]
[f]
1
The dr was determined by H NMR.
The er refers to the major trans-diastereomer and was determined by HPLC.
In the absence of MS.
4ꢂ MS was used.
Performed at 08C.
Performed at 508C.
[g]
[h]
[i]
Catalyzed by 15 mol% 4f for 84 h.
Catalyzed by 15 mol% 4f in the mixed solvent of 1,4-dioxane and toluene (1:1 v/v) for 84 h.
[j]
value but would decrease the yield (entries 4 and 5 vs duced enantioselectivity of 93:7 er (entry 11 vs.
entry 1). Finally, the reagent ratio was carefully tuned entry 10). Notwithstanding, these conditions are rela-
in order to enhance the enantioselectivity as well as tively more suitable in terms of delivering a high ste-
the yield (entries 6–10). The presence of excess 3a reoselectivity with a fair yield. In fact, it seemed that
had no obvious effect on the reaction (entry 6 vs. the two factors of yield and enantioselectivity were
entry 1), while increasing the stoichiometry of 2a led somewhat restricted by each other, thereby high yield
to an improved enantioselectivity but with a dramati- accompanied with excellent enantioselectivity could
cally decreased yield (entries 7 vs. entry 1). And using hardly be achieved simultaneously and a compromise
an excess of 2a and 3a at the same time did not bene- between them should be made. Thus, in an attempt to
fit the reaction (entry 8 vs. entry 1). When the stoi- further increase the yield with minimally reduced
chiometries of 1a and 2a were increased simultane- enantioselectivity, a mixed solvent of 1,4-dioxane and
ously, the enantioselectivity was improved but still toluene (1:1 v/v) was utilized at the ratio of 2:1:2,
with poor yield and decreased diastereoselectivity which rendered the reaction to proceed in a high
(entries 9 vs. entry 1). However, elevating the stoi- yield of 73% with good enantioselectivity of 88:12 er
ACHTUNGTRENNUNG
(entry 10 vs. entry 1). So, the most suitable ratio of ried out an investigation on the substrate scope of
1a:2a:3a was set as 2:1:2 (entry 1) or 3.5:1:3.5 anilines 1 by the reaction with methyl acetoacetate 2a
(entry 10). When the catalyst loading was increased to and 4-bromobenzaldehyde 3a (Table 3). The results
15 mol% at the ratio of 3.5:1:3.5, the yield was en- disclosed that a wide range of anilines including elec-
hanced from 42% to 59% albeit with a slightly re- tronically poor, neutral and rich ones served as appro-
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Catalytic Asymmetric Five-Component Tandem Reaction
Table 3. The substrate scope of anilines.[a]
Entry
5
R
Yield [%][b]
dr[c]
er[d]
1
5aaa
5baa
5caa
5daa
5eaa
5faa
5gaa
5haa
5iaa
4-OMe (1a)
4-OEt (1b)
4-OPh (1c)
3,4-OCH2CH2O (1d)
4-CH3 (1e)
H (1f)
4-F (1g)
3-F (1h)
4-CN (1i)
59
52
62
47
58
51
90:10
76:24
76:24
79:21
84:16
85:15
93:7
87:13
83:17
88:12
90:10
90:10
2[e]
3
4
5[e]
6[e]
7
59 (46[e])
58 (48[e])
43
79:21 (82:18[e])
89:11 (93:7[e])
>99:1
84:16 (89:11[e])
89:11 (91:9[e])
87:13
8
9[f]
[a]
Unless indicated otherwise, the reaction was carried out on a 0.1-mmol scale in the mixed solvent of 1,4-dioxane and tolu-
ene (1:1 v/v, 1 mL) with 3ꢂ MS (100 mg) for 84 h, and the ratio of 1:2a:3a was 2:1:2.
Isolated yield.
The dr refers to the ratio of trans-diastereomer to cis-diastereomer and was determined by H NMR.
The er refers to the major trans-diastereomer and was determined by HPLC.
Catalyzed by 12 mol% 4f.
[b]
[c]
[d]
[e]
[f]
1
Catalyzed by 18 mol% 4f.
priate substrates, providing structurally diverse tetra- 90:10 dr, 84:16 to 93:7 er). In general, there was no
hydropyridines 5 in good stereoselectivities (76:24 to remarkable difference between electronically poor al-
>99:1 dr, 83:17 to 93:7 er). In general, the electronic dehydes and electronically rich ones with regard to
nature of the substituents of the anilines had no sig- enantioselectivity, but the former delivered higher
nificant influence on the enantioselectivity, but the yields than the latter in most cases (entries 1–7 vs. en-
size and position of the substituents had some delicate tries 9–12). In the cases of halogen-substituted benzal-
effect on the enantioselectivity in some cases. For in- dehydes, the enantioselectivity was evidently en-
stance, when increasing the size of an alkoxy group, hanced from 89:11 to 93:7 er when increasing the
the enantioselectivity was decreased from 93:7 to atomic radius of the halogen (entries 1–3). As ob-
83:17 er (entries 1–3). And meta-substituted fluoroani- served before, lowering the catalyst loading greatly
line delivered higher er value than its para-substituted improved the enantioselectivity albeit with a de-
counterpart (entry 8 vs. entry 7). Besides, better dia- creased yield (entry 1, in parentheses), while increas-
stereo- and enantioselectivities could be achieved ing the catalyst loading remarkably enhanced the
when lowering the catalyst loading, albeit with de- yield but with an erosion of the enantioselectivity
creased yields (entries 7 and 8, in parentheses). Im- (entry 10, in parentheses). Moreover, benzaldehydes
portantly, even if an aniline bearing strong electron- with strong electron-donating groups such as 4-me-
withdrawing group was applied, excellent diastereose- thoxybenzaldehyde 3k could also be employed to the
lectivity (>99:1 dr) and good enantioselectivity (87:13 reaction in spite of the low reactivity associated with
er) could also be obtained as exemplified by 4-cya- such a aldehyde,[10a,c] delivering the desired tetrahy-
noaniline (entry 9).
dropyridine 5fak in good stereoselectivity (86:14 dr,
Next, the generality for aldehydes 3 was examined 90:10 er, entry 11). Notably, this protocol could also
by the reaction with 4-methoxyaniline 1a and methyl be applied to heteroaromatic aldehydes as exempli-
acetoacetate 2a. As shown in Table 4, this protocol is fied by thiophene-2-carbaldehyde 3l in a good stereo-
applicable to a wide scope of aldehydes including selectivity albeit with an unsatisfactory yield
benzaldehydes bearing either of an electronically (entry 13).
poor, neutral, or rich substituent, and a heteroaromat-
Finally, the substrate scope with respect to b-keto
ic aldehyde in fair to good stereoselectivities (67:33 to esters 2 was explored by the reactions with 4-meth-
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Table 4. The substrate scope of aldehydes.[a]
Entry
5
Ar
Yield [%][b]
dr[c]
er[d]
1
5aab
5aac
5aaa
5aad
5aae
5aaf
5aag
5aah
5aai
5aaj
5fak
5fai
4-FC6H4 (3b)
58 (39[e])
50
59
63
59
65
60
46
79:21 (76:24[e])
77:23
90:10
76:24
77:23
67:33
76:24
78:22
89:11 (93:7[e])
90:10
93:7
90:10
87:13
84:16
84:16
89:11
2[e]
3
4-ClC6H4 (3c)
4-BrC6H4 (3a)
4-CNC6H4 (3d)
4-MeO2CC6H4 (3e)
3,4-F2C6H3 (3f)
3-NO2C6H4 (3g)
C6H5 (3h)
4-MeC6H4 (3i)
3-MeC6H4 (3j)
4-MeOC6H4 (3k)
4-MeC6H4 (3i)
2-thiophenyl (3l)
4[e]
5
6[f]
7[e]
8
9[f]
10
51
82:18
87:13
42 (64[f])
38
81:19 (82:18[f])
86:14
90:10 (86:14[f])
90:10
11[g]
12[f,g]
13[h]
68
38
86:14
76:24
86:14
87:13
5aal
[a]
Unless indicated otherwise, the reaction was carried out on a 0.1 mmol scale in the mixed solvent of 1,4-dioxane and tolu-
ene (1:1 v/v, 1 mL) with 3ꢂ MS (100 mg) for 84 h, and the ratio of 1a:2a:3 was 2:1:2.
Isolated yield.
The dr refers to the ratio of trans-diastereomer to cis- diastereomer and was determined by H NMR.
The er refers to the major trans-diastereomer and was determined by HPLC.
Catalyzed by 12 mol% 4f.
Catalyzed by 18 mol% 4f.
Aniline 1f was employed as substrate instead of 4-methoxyaniline 1a.
Catalyzed by 20 mol% 4f.
[b]
[c]
[d]
[e]
[f]
1
[g]
[h]
Table 5. The substrate scope of b-keto esters.[a]
Entry
5
R
Yield [%][b]
dr[c]
er[d]
1
2
5aaa
5aba
5aca
5ada
5aea
5afa
Me (2a)
Et (2b)
allyl (2c)
i-Pr (2d)
t-Bu (2e)
Bn (2f)
59
64
59
80
50
64
90:10
88:12
77:23
80:20
90:10
76:24
93:7
84:16
90:10
87:13
95:5
3[e]
4[e]
5
6[e]
88:12
[a]
Unless indicated otherwise, the reaction was carried out on a 0.1-mmol scale in 1,4-dioxane (1 mL) with 3ꢂ MS (100 mg)
for 84 h, and the ratio of 1a:2:3a was 3.5:1:3.5.
Isolated yield.
The dr refers to the ratio of trans-diastereomer to cis-diastereomer and was determined by H NMR.
The er refers to the major trans-diastereomer and was determined by HPLC.
[b]
[c]
[d]
[e]
1
Catalyzed by 18 mol% 4f in the mixed solvent of 1,4-dioxane and toluene (1:1 v/v), and the ratio of 1a:2:3a was 2:1:2.
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Catalytic Asymmetric Five-Component Tandem Reaction
Figure 2. X-ray structure of tetrahydropyridine 5aaa.
ACHTUNGTRENNUNGoxyaniline 1a and 4-bromobenzaldehyde 3a. As indi- quently underwent a [4+2] reaction with the inter-
cated in Table 5, this protocol is amenable to various mediate 7 to provide the densely functionalized tetra-
b-keto esters with different ester groups including hydropyridines 5. In the proposed transition state of
alkyl, allyl and benzyl ones, affording products 5 in the [4+2] reaction, the 3,3’-bi(p-chlorophenyl)phos-
good to high stereoselectivities (76:24 to 90:10 dr, phoric acid 4f acted as a bifunctional catalyst to acti-
84:16 to 95:5 er). Among alkyl-substituted esters (en- vate both the diene 7 and the E-imine 8 by hydrogen-
tries 1, 2 and 4, 5), the tert-butyl ester delivered the bonding interactions. Then a stereoselective [4+2] re-
highest stereoselectivity (90:10 dr, 95:5 er, entry 5),
and the isopropyl ester was better than the ethyl ester
with regard to enantioselectivity (entry 4 vs. entry 2).
Apart from alkyl esters, allyl and benzyl ones could
also participate in the reaction with good enantiose-
lectivities (entries 3 and 6).
The absolute configuration of compound 5aaa (98:2
er after recrystallization) was unambiguously deter-
mined to be (2R,6S) by single-crystal X-ray diffraction
analysis (Figure 2).[13] Moreover, the relative configu-
ration of compound 5aaa was confirmed to be trans
1
by its X-ray structure and comparison of its H NMR
spectrum with that of the racemic trans-product.[8,10f]
The relative and absolute configurations of other
functionalized tetrahydropyridines 5 were assigned by
analogy.
Based on our experimental results and reports on
non-enantioselective reactions,[8–10] we proposed a pos-
sible reaction pathway to explain the chemistry and
the stereoselectivity of this catalytic asymmetric five-
component reaction (Scheme 2). Initially, the reaction
of anline 1 with b-keto ester 2 in the presence of
chiral phosphoric acid 4f generated enamine 6, which
then condensed with aldehyde 3 in a Knoevenagel-
type reaction to produce a diene species 7, a key in-
termediate in the tandem reaction. Simultaneously,
4f-catalyzed condensation of aniline 1 with aldehyde
Scheme 2. Proposed reaction mechanism and transition
3 afforded the corresponding imine 8, which subse- state.
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Scheme 3. The isolation of intermediate 7.
action occurred because of the chiral environment reoselectivity of the intermediate-involved reaction
created by the (R)-BINOL backbone and the congest- was inferior to that of the five-component one-pot re-
ed 3,3’-substitutents of the catalyst 4f, thereby offer- action, the generation of tetrahydropyridine 5aaa
ing the experimentally observed (2R,6S)-configured from intermediate 7 and in situ formed imine 8 sup-
product 5.
ported the [4+2] reaction pathway to some extent.
However, in previous reports on non-enantioselec-
To explain the experimentally observed inferior ste-
tive reactions,[8–10] the key intermediate 7 was not iso- reoselectivity and reactivity of the reaction between
lated or observed, which could hardly testify the pro- intermediate 7 and in situ formed imine 8, we moni-
posed [4+2] process of the reaction. In an attempt to tored the mole ratio of intermediates 8 to 7 during
clarify the reaction pathway, we performed an in- the formation of 5aaa in the five-component reaction.
depth study on the reaction mechanism. Fortunately, As illustrated in Table 6 and Figure 3, during the
we observed and isolated the key intermediate 7 course of the five-component reaction (84 h), the
during the reaction process. As shown in Scheme 3, in amounts of intermediates 7 and 8 were constantly
the one-pot five-component model reaction, the de- changing, which led to the remarkable variation in
sired product 5aaa was afforded in 46% yield, accom- the mole ratio of intermediates 8 to 7. The five-com-
panied by the isolation of intermediate 7 in 19% yield ponent reaction was a dynamic process, i.e., the for-
and imine 8 in 13% yield. The structure of intermedi- mation of 5aaa would consume intermediates 7 and 8,
ate 7 was unambiguously confirmed by 1H and which rendered the starting materials to continuously
13C NMR, IR and HR-mass spectra. The isolation of produce more amounts of the intermediates. While in
this key intermediate demonstrated the high possibili- the reaction of intermediate 7 with in situ formed
ty of the [4+2] reaction pathway.
imine 8 (Scheme 4), the starting concentration and
In order to further prove the proposed [4+2] reac- mole ratio of the reactants were fixed and no more in-
tion pathway, the intermediate 7 was subjected to the termediate 7 could be generated during the reaction
reaction with imine 8 generated in situ from aniline process. So, there existed a great difference in the
1a and aldehyde 3a under the optimal reaction condi- concentrations and mole ratios of the two intermedi-
tions (Scheme 4). As expected, the reaction proceed- ates (7 and 8) between the five-component reaction
ed smoothly to afford the desired product 5aaa in and the intermediate-involved stepwise process.
43% yield, which was a little lower than that of the
Then, to investigate the influence of mole ratio on
five-component one-pot reaction. Although the ste- the intermediate-involved stepwise reaction, we car-
Scheme 4. The reaction between intermediate 7 and in situ formed imine.
8
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Catalytic Asymmetric Five-Component Tandem Reaction
Table 6. The mole ratio of intermediates 8 to 7 during the formation of 5aaa in the five-component reaction.[a]
Entry
Time [h]
8:7[b]
8
[c] (mmol)
7[c] (mmol)
5aaa
dr[e]
Yield [%][d]
er[f]
1
2
3
4
5
6
7
12
24
36
48
60
72
84
22.2:1
21.9:1
7.5:1
5.5:1
7.4:1
5.6:1
4.2:1
71.0
56.9
61.7
55.2
68.3
62.1
43.1
3.2
2.6
8.2
10.1
9.2
38
38
41
56
59
60
73
86:14
89:11
90:10
87:13
85:15
85:15
88:12
91:9
90:10
90:10
89:11
89:11
88:12
88:12
11.1
10.3
[a]
Unless indicated otherwise, the reaction was carried out on a 0.1-mmol scale in the mixed solvent of 1,4-dioxane and tolu-
ene (1:1 v/v, 1 mL) with 3ꢂ MS (100 mg) for a given time, and the ratio of 1a:2a:3a was 2:1:2.
The mole ratio of intermediates 7 to 8 at the specified time points.
Determined by HPLC using an internal standard.
[b]
[c]
[d]
[e]
[f]
Isolated yield.
1
The dr refers to the ratio of trans-diastereomer to cis-diastereomer and was determined by H NMR.
The er refers to the major trans-diastereomer and was determined by HPLC.
ried out the reaction of intermediate 7 with in situ tion could hardly imitate the real and continuously
formed imine 8 under different mole ratios. As shown changeable concentrations and mole ratios of the in-
in Table 7, the mole ratio of the intermediates indeed termediates in situ generated from the five-compo-
imposed an obvious effect on the stereoselectivity and nent reaction, thereby resulting in the observed inferi-
reactivity. Encouragingly, when the mole ratio of or stereoselectivity and reactivity.
1a:3a:7 was 2:2:1, the enantioselectivity of 5aaa was
Moreover, we also tried the synthesis of the inter-
improved to 72:28 er (entry 3), which was closer to mediate 7 via stepwise procedures according to the
the result of the five-component reaction (89:11 er, proposed mechanism (Scheme 5 and Scheme 6). As
entry 7). But the intermediate-involved stepwise reac- shown in Scheme 5, 4f-catalyzed condensation of 1a
Figure 3. The amounts and the mole ratio of intermediates detected during the course of five-component reaction.
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Feng Shi et al.
FULL PAPERS
Table 7. The effect of mole ratios on the reaction between intermediate 7 and in situ formed imine.[a]
Entry
1a:3a:7
Yield [%][b]
dr[c] (trans:cis)
er[d]
1[e]
2
3
4
5
1:1:1
1.5:1.5:1
2:2:1
43
27
37
55
49
39
56
62:38
73:27
66:34
60:40
63:37
62:38
87:13
63:37
58:42
72:28
61:39
69:31
64:36
89:11
3:3:1
3.5:3.5:1
5:5:1
6
7
control[f]
[a]
Unless indicated otherwise, the reaction was carried out on a 0.05-mmol scale in the mixed solvent of 1,4-dioxane and tol-
uene (1:1 v/v, 0.5 mL) with 3 ꢂ MS (50 mg) for 48 h.
Isolated yield.
The dr refers to the ratio of trans-diastereomer to cis-diastereomer and was determined by H NMR.
The er refers to the major trans-diastereomer and was determined by HPLC.
The reaction was carried out on a 0.1-mmol scale for 84 h.
The control experiment refers to the five-component reaction with the same reaction time of 48 h, which was illustrated
in Table 6, entry 4.
[b]
[c]
[d]
[e]
[f]
1
Scheme 5. The synthesis of intermediate 7 via stepwise procedures at 358C.
Scheme 6. The synthesis of intermediate 7 via stepwise procedures at 908C.
and 2a at 358C afforded enamine 6 in 32% yield, but yield), but the second step was still very sluggish, af-
the subsequent treatment of enamine 6 with 3a under fording the desired diene 7 in an extremely low yield
the same reaction conditions could hardly offer the of 6%.
desired intermediate 7 after 24 h.
On the contrary, the intermediate 7 was isolated in
Then we tried the same stepwise procedures at an 19% yield via the one-pot reaction as mentioned
elevated temperature of 908C in the presence of ben- above (Scheme 3). So, we further tried the one-pot
zoic acid (Scheme 6). At this reaction temperature, protocol to prepare intermediate 7 at 508C in the
the enamine formation was more efficient (65% presence of racemic phosphoric acid 4k (Scheme 7).
10
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Catalytic Asymmetric Five-Component Tandem Reaction
Scheme 7. The synthesis of intermediate 7 via a one-pot protocol.
Scheme 8. The comparison between stepwise and one-pot protocols.
In the cases of Scheme 6 and Scheme 7, benzoic acid
On the basis of above investigations, we compared
or racemic phosphoric acid 4k was employed as cata- the efficiency of the stepwise protocol with that of the
lyst in order to save up a large amount of CPA 4f, one-pot five-component protocol in the synthesis of
since no chiral centers would be generated in inter- chiral tetrahydropyridine 5aaa. As demonstrated in
mediate 7. As illustrated in Scheme 7, the one-pot re- Scheme 8, the one-pot five-component approach was
action afforded the desired diene 7 in 21% yield ac- much superior to stepwise procedures both in reactivi-
companied with the formation of racemic 5aaa. The ty and in stereoselectivity. This comparison also
yield of intermediate 7 in this one-pot protocol was strongly manifested the tremendous advantages of
much higher than those of the stepwise procedures, asymmetric multicomponent reactions over multistep
demonstrating the superiority of one-pot multicompo- ones.
nent reactions to multistep ones. The relatively higher
efficiency of such a protocol may be attributed to the
dynamic equilibrium existing in the multicomponent Conclusions
reaction: the formation of rac-5aaa would consume
intermediate 7, which rendered the reaction to contin- In summary, we have established the first catalytic
uously proceed toward the generation of more asymmetric five-component reactions of b-keto esters,
amounts of intermediate 7.
aromatic aldehydes and anilines in the presence of
a chiral phosphoric acid. This protocol combines the
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FULL PAPERS
dine-3-carboxylate (5aaa): Flash column chromatography
eluent, petroleum ether/ethyl acetate=18/1; reaction time=
84 h; yield: 40.0 mg (59%); 90:10 dr; white solid; mp 215–
2178C; [a]2D0: +43.0 (c 0.27, CHCl3). 1H NMR (CDCl3,
400 MHz): d=10.09 (s, 1H), 7.41–7.36 (m, 4H), 7.15 (d, J=
8.3 Hz, 2H), 7.00 (d, J=8.4 Hz, 2H), 6.70–6.64 (m, 4H),
6.40–6.32 (m, 4H), 6.19 (s, 1H), 4.96–4.94 (m, 1H), 3.88 (s,
3H), 3.77 (s, 3H), 3.67 (s, 3H), 2.72 (dd, J=15.3, 5.6 Hz,
1H), 2.61 (dd, J=15.3, 3.0 Hz, 1H); 13C NMR (CDCl3,
100 MHz): d=168.3, 158.0, 156.6, 151.4, 143.1, 141.9, 140.9,
131.6, 131.2, 130.4, 128.6, 128.3, 127.7, 120.8, 120.1, 114.6,
114.4, 114.1, 96.4, 57.3, 55.6, 55.6, 55.4, 51.0, 33.6; IR (KBr):
n=3364, 3261, 3046, 2924, 2852, 1726, 1656, 1605, 1510,
1485, 1458, 1402, 1245, 1182, 1071, 1038, 1010, 979, 927, 883,
merits of asymmetric organocatalysis and multicom-
ponent reactions, tolerating a wide range of substrates
to furnish densely functionalized tetrahydropyridines
with concomitant generation of five s bonds and two
chiral centers in good to high diastereo- and enantio-
selectivities (up to >99:1 dr, 95:5 er). Besides, a diene
species as the key intermediate of the reaction has
been firstly isolated and synthesized. And this inter-
mediate was subjected to further condensation with
an in situ generated imine to afford the desired tetra-
hydropyridine, which supported the proposed tandem
[4+2] reaction pathway to some extent. Moreover,
the comparison between the stepwise protocol and
the five-component one-pot approach has demon-
strated the much higher efficiency of the latter over
the former. This five-component approach not only
provides an easy access to biologically relevant chiral
tetrahydropyridines with structural diversity, but also
greatly enriches the contents of catalytic enantioselec-
tive multicomponent reactions.
811, 736 cmÀ1
; ESI-FT-MS: m/z=677.0652, calcd. for
(C33H30Br2N2O4 +H)+: 677.0651. Enantiomeric ratio: 93:7,
determined by HPLC (Daicel Chirapak AD-H, hexane/2-
propanol=90/10, flow rate 1.0 mLminÀ1, T=308C, 254 nm):
tR =9.488 min (major), tR =30.581 min (minor).
AHCTUNGTREG(NNUN 2R,6S)-Methyl 2,6-bis(4-bromophenyl)-1-(4-ethoxyphen-
yl)-4-(4-ethoxyphenylamino)-1,2,5,6-tetrahydropyridine-3-
carboxylate (5baa): Flash column chromatography eluent,
petroleum ether/ethyl acetate=25/1; reaction time=84 h;
yield: 36.7 mg (52%); 76:24 dr; white solid; mp 213–2158C;
1
Experimental Section
[a]2D0: +38.7 (c 0.2, CHCl3). H NMR (CDCl3, 400 MHz): d=
10.08 (s, 1H), 7.39–7.36 (m, 4H), 7.14 (d, J=8.2 Hz, 2H),
6.99 (d, J=8.4 Hz, 2H), 6.68–6.64 (m, 4H), 6.37–6.31 (m,
4H), 6.19 (s, 1H), 4.95–4.94 (m, 1H), 3.97 (q, J=7.0 Hz,
2H), 3.90–3.85 (m, 5H), 2.71 (dd, J=15.3, 5.6 Hz, 1H), 2.61
(dd, J=15.3, 3.0 Hz, 1H), 1.40 (t, J=7.0 Hz, 3H), 1.32 (t,
J=7.0 Hz, 3H); 13C NMR (CDCl3, 100 MHz): d=168.3,
157.4, 156.7, 150.7, 143.2, 142.0, 140.9, 131.6, 131.2, 130.2,
128.6, 128.3, 127.7, 120.8, 120.1, 115.3, 114.6, 114.5, 96.4,
63.8, 63.6, 57.3, 55.6, 51.0, 33.5, 14.9, 14.7; IR (KBr): n=
3362, 3241, 3166, 3046, 2978, 2854, 1727, 1656, 1605, 1510,
1481, 1454, 1397, 1242, 1186, 1113, 1070, 1048, 1009, 979,
General Remarks
NMR spectra were measured at 400 and 100 MHz, respec-
tively. The solvent used for NMR spectroscopy was CDCl3,
using tetramethylsilane as the internal reference. HR-MS
were recorded on a LTQ-Orbitrap mass spectrometer (ioni-
zation mode: ESI+). The enantiomeric ratio (er) was deter-
mined by chiral high-performance liquid chromatography
(chiral HPLC). The chiral columns used for the determina-
tion of enantiomeric ratios by chiral HPLC were Chiralpak
AD-H, IA, OD-H and IC columns. Optical rotation values
were measured with instruments operating at l=589 nm,
corresponding to the sodium D line at the temperatures in-
dicated. Analytical grade solvents for the column chroma-
tography and commercially available reagents were used as
received. Toluene was dried and distilled prior to use.
808, 736 cmÀ1
; ESI-FT-MS: m/z=705.0953, calcd. for
(C35H34Br2N2O4 +H)+: 705.0964. Enantiomeric ratio: 87:13,
determined by HPLC (Daicel Chirapak AD-H, hexane/2-
propanol=70/30, flow rate 1.0 mLminÀ1, T=308C, 254 nm):
tR =5.997 min (major), tR =14.421 min (minor).
A
2,6-bis(4-bromophenyl)-1-(4-phenoxy-
phenyl)-4-(4-phenoxyphenylamino)-1,2,5,6-tetrahydropyri-
dine-3-carboxylate (5caa): Flash column chromatography
eluent, petroleum ether/ethyl acetate=28/1; reaction time=
84 h; yield: 50.1 mg (62%); 76:24 dr; white solid; mp 99–
1018C; [a]2D0: +26.7 (c 0.3, CHCl3). 1H NMR (CDCl3,
400 MHz): d=10.16 (s, 1H), 7.40 (dd, J=8.4, 1.7 Hz, 4H),
7.36–7.32 (m, 2H), 7.25–7.22 (m, 2H), 7.17 (d, J=8.4 Hz,
2H), 7.12 (t, J=7.4 Hz, 1H), 7.04–6.96 (m, 5H), 6.88–6.86
(m, 2H), 6.80–6.76 (m, 4H), 6.40 (d, J=9.2 Hz, 2H), 6.36
(d, J=8.7 Hz, 2H), 6.27 (s, 1H), 5.04–5.03 (m, 1H), 3.91 (s,
3H), 2.79 (dd, J=15.2, 5.6 Hz, 1H), 2.69 (dd, J=15.2,
2.6 Hz, 1H); 13C NMR (CDCl3, 100 MHz): d=167.2, 157.5,
155.7, 155.1, 154.6, 146.4, 142.0, 141.7, 140.5, 131.61, 130.7,
130.3, 128.8, 128.4, 127.4, 127.1, 126.6, 122.6, 121.1, 120.0,
119.5, 119.3, 118.2, 117.9, 116.4, 112.9, 96.0, 56.5, 54.2, 50.1,
32.5; IR (KBr): n=3439, 3244, 3044, 2921, 2851, 1720, 1656,
1601, 1506, 1487, 1459, 1403, 1370, 1317, 1239, 1187, 1107,
1071, 1010, 978, 864, 817, 791, 750, 692 cmÀ1; ESI- FT-MS:
m/z=801.0953, calcd. for (C43H34Br2N2O4 +H)+: 801.0964.
Enantiomeric ratio: 83:17, determined by HPLC (Daicel
General Procedure for the Asymmetric Five-
Component Reactions
After a solution of aniline 1 (0.2 mmol), b-keto ester 2
(0.1 mmol), the catalyst 4f (0.015 mmol), and 3ꢂ molecular
sieves (100 mg) in the mixed toluene/1,4-dioxane (1:1 v/v,
0.5 mL) had been stirred at 358C for 30 mins, the solution
of aromatic aldehyde 3 (0.2 mmol) in the mixed toluene/1,4-
dioxane (1:1 v/v, 0.5 mL) was added. In some cases as indi-
cated in Table 3, toluene was used as solvent and the ratio
of 1:2:3 was changed to 3.5:1:3.5. After being stirred at
358C for 84 h, the reaction mixture was filtered to remove
molecular sieves and the solid powder was washed with
ethyl acetate. The resultant solution was concentrated under
reduced pressure to give a residue, which was purified
through flash column chromatography on silica gel to afford
pure product 5.
A
2,6-bis(4-bromophenyl)-1-(4-methoxy-
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Catalytic Asymmetric Five-Component Tandem Reaction
Chirapak AD-H, hexane/2-propanol=70/30, flow rate
1.0 mLminÀ1, T=308C, 254 nm): tR =6.454 min (major), tR =
13.696 min (minor).
97.4, 57.4, 54.8, 51.1, 33.6; IR (KBr): n=3437, 2972, 2918,
2877, 1654, 1609, 1504, 1437, 1408, 1317, 1256, 1182, 1022,
952, 881, 788, 741 cmÀ1; ESI-FT-MS: m/z=617.0434, calcd.
for (C31H26Br2N2O2 +H)+: 617.0439. Enantiomeric ratio:
90:10, determined by HPLC (Daicel Chirapak AD-H,
hexane/2-propanol=95/5, flow rate 1.0 mLminÀ1, T=308C,
254 nm): tR =7.655 min (major), tR =15.961 min (minor).
A
ACHTUNGTRNE[NUNG 1,3]dioxol-5-yl)-4-(benzo[d]-
ACHTUNGTRENNUNG
hydropyridine-3-carboxylate (5daa): Flash column chroma-
tography eluent, petroleum ether/ethyl acetate=23/1; reac-
tion time=84 h; yield: 33.2 mg (47%); 79:21 dr; white solid;
mp 222–2248C; [a]D20: +23.5 (c 0.6, CHCl3). 1H NMR
(CDCl3, 400 MHz): d=10.04 (s, 1H), 7.39 (t, J=8.3 Hz,
4H), 7.13 (d, J=8.3 Hz, 2H), 7.00 (d, J=8.4 Hz, 2H), 6.55
(dd, J=10.6, 8.3 Hz, 2H), 6.16 (s, 1H), 6.09 (d, J=2.5 Hz,
1H), 5.94 (dd, J=5.2, 1.4 Hz, 2H), 5.83–5.82 (m, 3H), 5.78
(dd, J=5.5, 1.4 Hz, 2H), 4.95–4.94 (m, 1H), 3.89 (s, 3H),
2.73 (dd, J=15.3, 5.6 Hz, 1H), 2.63 (dd, J=15.3, 2.9 Hz,
1H); 13C NMR (CDCl3, 100 MHz): d=168.2, 156.4, 148.2,
147.8, 146.1, 142.8, 142.5, 141.6, 139.0, 131.7, 131.4, 131.2,
128.5, 128.2, 121.0, 120.2, 119.7, 108.3, 107.9, 107.8, 105.4,
101.5, 100.5, 96.7, 96.3, 57.7, 55.8, 51.0, 33.6; IR (KBr): n=
3360, 3246, 3168, 3050, 2922, 2854, 1729, 1657, 1598, 1488,
1455, 1401, 1372, 1323, 1253, 1184, 1100, 1068, 1038, 1010,
AHCTUNGTREG(NNUN 2R,6S)-Methyl 2,6-bis(4-bromophenyl)-1-(4-fluorophen-
yl)-4-(4-fluorophenylamino)-1,2,5,6-tetrahydropyridine-3-
carboxylate (5gaa): Flash column chromatography eluent,
petroleum ether/ethyl acetate=50/1; reaction time=84 h;
yield: 38.3 mg (59%); 79:21 dr; pale yellow solid; mp 221–
2238C; [a]2D0: +33.4 (c 0.3, CHCl3). 1H NMR (CDCl3,
400 MHz): d=10.14 (s, 1H), 7.42–7.39 (m, 4H), 7.13 (d, J=
8.2 Hz, 2H), 6.99 (d, J=8.2 Hz, 2H), 6.89–6.83 (m, 2H),
6.81–6.75 (m, 2H), 6.38–6.33 (m, 4H), 6.23 (s, 1H), 5.00–
4.99 (m, 1H), 3.91 (s, 3H), 2.77 (dd, J=15.3, 5.7 Hz, 1H),
2.61 (dd, J=15.3, 2.7 Hz, 1H); 13C NMR (CDCl3, 100 MHz):
d=168.2, 160.9 (J=245.0 Hz), 155.9, 155.4 (J=234.8 Hz),
154.2, 142.9, 142.5, 141.4, 133.5, 133.5, 131.8, 131.4, 128.4,
128.1, 128.0, 127.9, 121.1, 120.4, 116.0, 115.7, 115.5, 115.3,
113.9, 113.8, 97.3, 57.5, 55.4, 51.2, 33.5; IR (KBr): n=3361,
3241, 3167, 3052, 2951, 2923, 2852, 1721, 1658, 1610, 1509,
1457, 1402, 1370, 1319, 1258, 1186, 1071, 1010, 979, 953, 927,
887, 846, 809, 737 cmÀ1; ESI-FT-MS: m/z=653.0250, calcd.
for (C31H24Br2F2N2O2 +H)+: 653.0251. Enantiomeric ratio:
84:16, determined by HPLC (Daicel Chirapak IA, hexane/2-
propanol=70/30, flow rate 1.0 mLminÀ1, T=308C, 254 nm):
tR =5.157 min (major), tR =10.597 min (minor).
976, 932, 894, 847, 814, 736 cmÀ1
; ESI-FT-MS: m/z=
705.0229, calcd. for (C33H26Br2N2O6 +H)+: 705.0236. Enan-
tiomeric ratio: 88:12, determined by HPLC (Daicel Chira-
pak
AD-H,
hexane/2-propanol=70/30,
flow
rate
1.0 mLminÀ1, T=308C, 254 nm): tR =8.111 min (major), tR =
16.123 min (minor).
ACHTUNGTRENNUNG
Flash column chromatography eluent, petroleum ether/ethyl
acetate=85/1; reaction time=84 h; yield: 37.5 mg (58%);
84:16 dr (inseparable diastereomers); yellow solid; mp 207–
2098C; [a]2D0: +17.5 (c 0.4, CHCl3). 1H NMR (CDCl3,
400 MHz): d=10.16 (s, 1H), 7.40–7.37 (m, 4H), 7.17 (d, J=
8.2 Hz, 2H), 7.00 (d, J=8.4 Hz, 2H), 6.96 (d, J=8.0 Hz,
2H), 6.88 (d, J=8.4 Hz, 2H), 6.36 (d, J=8.7 Hz, 2H), 6.29–
6.27 (m, 3H), 5.04–5.03 (m, 1H), 3.91 (s, 3H), 2.77 (dd, J=
15.2, 5.5 Hz, 1H), 2.70 (dd, J=15.2, 2.8 Hz, 1H), 2.29 (s,
3H), 2.17 (s, 3H); 13C NMR (CDCl3, 100 MHz): d=168.3,
156.3, 144.3, 143.2, 141.7, 136.0, 134.9, 131.6, 131.3, 129.6,
128.4, 128.2, 125.9, 125.8, 123.0, 120.8, 120.1, 112.9, 96.9,
57.3, 54.9, 51.0, 33.5, 20.9, 20.1; IR (KBr): n=3358, 3243,
3169, 3051, 2955, 2924, 2853, 2219, 1728, 1658, 1599, 1511,
1487, 1457, 1403, 1372, 1325, 1178, 1104, 1070, 1033, 1010,
977, 885, 811, 736 cmÀ1; ESI-FT-MS: m/z=645.0757, calcd.
for (C33H30Br2N2O2 +H)+: 645.0752. Enantiomeric ratio:
90:10, determined by HPLC (Daicel Chirapak AD-H,
hexane/2-propanol=85/15, flow rate 1.0 mLminÀ1, T=308C,
254 nm): tR =4.789 min (major), tR =9.925 min (minor).
ACHTUNGTREN(NUNG 2R,6S)-Methyl 2,6-bis(4-bromophenyl)-1-(3-fluorophen-
yl)-4-(3-fluorophenylamino)-1,2,5,6-tetrahydropyridine-3-
carboxylate (5haa): Flash column chromatography eluent,
petroleum ether/ethyl acetate=70/1; reaction time=84 h;
yield: 38.2 mg (58%); 89:11 dr; white solid; mp 199–2018C;
1
[a]2D0: +8.3 (c 0.2, CHCl3). H NMR (CDCl3, 400 MHz): d=
10.25 (s, 1H), 7.41 (dd, J=8.5, 2.8 Hz, 4H), 7.15–7.12 (m,
3H), 7.03–6.98 (m, 3H), 6.83 (td, J=8.3, 2.1 Hz, 1H), 6.35
(td, J=8.2, 2.0 Hz, 1H), 6.28 (s, 1H), 6.23–6.20 (m, 2H),
6.15 (dt, J=12.8, 2.3 Hz, 1H), 6.09 (dt, J=9.7, 2.2 Hz, 1H),
5.07 (d, J=3.5 Hz, 1H), 3.94 (s, 3H), 2.85 (dd, J=15.2,
5.6 Hz, 1H), 2.76 (dd, J=15.3, 2.5 Hz, 1H); 13C NMR
(CDCl3, 100 MHz): d=168.1, 164.5 (J=109.7 Hz), 162.0 (J=
115.4 Hz), 155.0, 148.2, 148.1, 142.0, 140.7, 139.2, 139.1,
131.9, 131.5, 130.2, 130.1, 130.0, 128.2, 127.9, 121.3, 121.0,
121.0, 120.6, 113.0, 112.8, 112.7, 112.5, 108.6, 103.6, 103.4,
100.3, 100.0, 98.3, 57.6, 55.0, 51.3, 33.5; IR (KBr): n=3440,
2920, 2853, 1724, 1659, 1602, 1490, 1443, 1403, 1370, 1334,
1257, 1187, 1162, 1118, 1072, 1010, 978, 955, 846, 817, 790,
752 cmÀ1
;
ESI-FT-MS:
m/z=653.0243,
calcd.
for
A
(C31H24Br2F2N2O2 +H)+: 653.0251. Enantiomeric ratio:
89:11, determined by HPLC (Daicel Chirapak AD-H,
hexane/2-propanol=70/30, flow rate 1.0 mLminÀ1, T=308C,
254 nm): tR =4.715 min (major), tR =7.309 min (minor).
nylamino)-1,2,5,6-tetrahydropyridine-3-carboxylate (5faa):
Flash column chromatography eluent, petroleum ether/ethyl
acetate=50/1; reaction time=84 h; yield: 31.4 mg (51%);
85:15 dr; white solid; mp 236–2378C; [a]2D0: +12.5 (c 0.3,
CHCl3). 1H NMR (CDCl3, 400 MHz): d=10.24 (s, 1H),
7.40–7.38 (m, 4H), 7.19–7.13 (m, 5H), 7.10–7.06 (m, 2H),
6.99 (d, J=8.4 Hz, 2H), 6.65 (t, J=7.3 Hz, 1H), 6.45 (d, J=
8.1 Hz, 2H), 6.42–6.40 (m, 2H), 6.33 (s, 1H), 5.08–5.07 (m,
1H), 3.92 (s, 3H), 2.82 (dd, J=15.2, 5.5 Hz, 1H), 2.74 (dd,
J=15.2, 2.6 Hz, 1H); 13C NMR (CDCl3, 100 MHz): d=
168.2, 156.0, 146.4, 142.9, 141.4, 137.6, 131.7, 131.3, 129.0,
129.0, 128.4, 128.1, 126.0, 125.7, 120.9, 120.2, 116.8, 112.9,
AHCTUNGTREG(NNUN 2R,6S)-Methyl 2,6-bis(4-bromophenyl)-1-(4-cyanophen-
yl)-4-(4-cyanophenylamino)-1,2,5,6-tetrahydropyridine-3-car-
boxylate (5iaa): Flash column chromatography eluent, pe-
troleum ether/ethyl acetate=6/1; reaction time=84 h; yield:
28.5 mg (43%); >99:1 dr; white solid; mp 248–2508C; [a]2D0:
1
À54.8 (c 0.4, CHCl3). H NMR (CDCl3, 400 MHz): d=10.46
(s, 1H), 7.48–7.41 (m, 6H), 7.34 (d, J=9.1 Hz, 2H), 7.11 (d,
J=8.3 Hz, 2H), 6.95 (d, J=8.4 Hz, 2H), 6.50 (dd, J=18.8,
8.8 Hz, 4H), 6.35 (s, 1H), 5.17–5.16 (m, 1H), 3.97 (s, 3H),
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
13
ÞÞ
These are not the final page numbers!

Feng Shi et al.
FULL PAPERS
2.98 (dd, J=15.3, 5.6 Hz, 1H), 2.83 (dd, J=15.3, 2.2 Hz,
1H); 13C NMR (CDCl3, 100 MHz): d=167.8, 153.4, 149.1,
141.7, 140.7, 139.4, 133.4, 133.2, 132.2, 131.8, 127.9, 127.7,
124.0, 121.8, 121.1, 119.8, 118.2, 113.0, 108.6, 100.5, 99.5,
57.5, 55.0, 51.8, 33.7; IR (KBr): n=3356, 3242, 3170, 3053,
2954, 2925, 2853, 2219, 1726, 1659, 1599, 1485, 1457, 1403,
1372, 1330, 1255, 1177, 1106, 1070, 1034, 1011, 976, 885, 813,
1H), 7.58–7.54 (m, 5H), 7.45 (d, J=8.4 Hz, 0.8H), 7.40 (d,
J=8.2 Hz, 2H), 7.31 (d, J=8.3 Hz, 0.8H), 7.23 (d, J=
8.2 Hz, 2H), 7.00–6.95 (m, 1H), 6.86–6.83 (m, 1H), 6.70–
6.61 (m, 5.5H), 6.36–6.28 (m, 5H), 5.59 (s, 0.3H), 5.07–5.05
(m, 1H), 4.48 (dd, J=11.7, 3.0 Hz, 0.3H), 3.90 (s, 3H), 3.78
(s, 1H), 3.77 (s, 3H), 3.68 (s, 1H), 3.67 (s, 3H), 3.64 (s, 1H),
2.76–2.65 (m, 2H), 2.64–2.61 (m, 0.4H), 2.48–2.41 (m, 1H);
13C NMR (CDCl3, 100 MHz): d=168.6, 168.1, 158.2, 157.8,
157.7, 157.2, 157.1, 156.7, 156.2, 155.96, 154.8, 152.3, 152.1,
151.9, 149.9, 149.7, 148.7, 148.3, 148.1, 143.6, 141.9, 140.2,
133.0, 132.4, 132.4, 132.2, 132.1, 132.0, 131.2, 130.8, 130.1,
129.9, 129.2, 128.4, 128.1, 128.0, 127.9, 127.5, 127.5, 127.4,
126.8, 126.5, 123.6, 122.0, 120.6, 119.0, 118.9, 118.8, 118.7,
118.5, 118.5, 114.7, 114.6, 114.5, 114.3, 114.2, 111.3, 111.2,
110.4, 95.7, 94.8, 64.2, 61.9, 57.5, 56.0, 55.6, 55.4, 55.37, 51.2,
50.8, 36.4, 33.4; IR (KBr): n=3358, 3243, 3167, 3051, 2927,
2840, 2227, 1728, 1653, 1605, 1510, 1457, 1407, 1369, 1246,
736 cmÀ1
;
ESI-FT-MS:
m/z=667.0338,
calcd.
for
(C33H24Br2N4O2 +H)+: 667.0344. Enantiomeric ratio: 87:13,
determined by HPLC (Daicel Chirapak AD-H, hexane/2-
propanol=70/30, flow rate 1.0 mLminÀ1, T=308C, 254 nm):
tR =8.574 min (major), tR =25.736 min (minor).
A
2,6-bis(4-fluorophenyl)-1-(4-methoxy-
phenyl)-4-(4-methoxyphenylamino)-1,2,5,6-tetrahydropyri-
dine-3-carboxylate (5aab): Flash column chromatography
eluent, petroleum ether/ethyl acetate=17/1; reaction time=
84 h; yield: 32.3 mg (58%); 79:21 dr; white solid; mp 224–
2268C; [a]2D0: +57.5 (c 0.2, CHCl3); 1H NMR (CDCl3,
400 MHz): d=10.12 (s, 1H), 7.23 (dd, J=8.4, 5.5 Hz, 2H),
7.11–7.08 (m, 2H), 7.00–6.93 (m, 4H), 6.68–6.65 (m, 4H),
6.41–6.33 (m, 2H), 6.35–6.33 (m, 2H), 6.23 (s, 1H), 5.00–
4.98 (m, 1H), 3.89 (s, 3H), 3.76 (s, 3H), 3.67 (s, 3H), 2.73
(dd, J=15.3, 5.6 Hz, 1H), 2.62 (dd, J=15.3, 3.1 Hz, 1H);
13C NMR (CDCl3, 100 MHz): d=168.4, 162.9 (J=44.6 Hz),
160.5 (J=43.7 Hz), 157.9, 156.8, 151.3, 141.1, 139.6, 138.5,
130.5, 128.3, 128.2, 128.1, 128.0, 127.7, 115.5, 115.3, 114.9,
114.7, 114.5, 114.1, 96.7, 57.2, 55.6, 55.4, 55.4, 50.9, 33.7; IR
(KBr): n=3250, 3048, 2996, 2924, 2851, 1732, 1654, 1605,
1509, 1457, 1415, 1373, 1243, 1182, 1158, 1070, 1036, 981,
1179, 1160, 1109, 1069, 1036, 979, 954, 893, 810, 736 cmÀ1
;
ESI FT-MS: m/z=571.2339, calcd. for (C35H30N4O4 +H)+:
571.2345. Enantiomeric ratio: 90:10, determined by HPLC
(Daicel Chirapak AD-H, hexane/2-propanol=70/30, flow
rate 1.0 mLminÀ1, T=308C, 254 nm): tR =10.681 min
(major), tR =47.932 min (minor).
Dimethyl
4,4’-[(2S,6R)-5-(methoxycarbonyl)-1-(4-meth-
oxyphenyl)-4-(4-methoxyphenylamino)-1,2,3,6-tetrahydro-
pyridine-2,6-diyl]dibenzoate (5aae): Flash column chroma-
tography eluent, petroleum ether/ethyl acetate=6/1; reac-
tion time=84 h; yield: 37.7 mg (59%); 77:23 dr; yellow
1
solid; mp 207–2098C; [a]2D0: +13.3 (c 0.4, CHCl3). H NMR
830 cmÀ1
;
ESI-FT-MS:
m/z=557.2256,
calcd.
for
(CDCl3, 400 MHz): d=10.09 (s, 1H), 7.95 (dd, J=8.4,
3.2 Hz, 4H), 7.37 (d, J=8.2 Hz, 2H), 7.22 (d, J=8.3 Hz,
2H), 6.64 (d, J=8.3 Hz, 4H), 6.37–6.27 (m, 5H), 5.09–5.08
(m, 1H), 3.92–3.90 (m, 9H), 3.75 (s, 3H), 3.65 (s, 3H), 2.77
(dd, J=15.4, 5.7 Hz, 1H), 2.68 (dd, J=15.4, 2.9 Hz, 1H);
13C NMR (CDCl3, 100 MHz): d=168.3, 167.0, 166.9, 158.0,
156.5, 151.5, 149.7, 148.3, 140.9, 130.3, 129.9, 129.6, 129.1,
128.4, 127.7, 126.7, 126.6, 114.6, 114.4, 114.1, 96.2, 57.8, 56.1,
55.6, 55.4, 52.1, 52.0, 51.0, 33.4; IR (KBr): n=3243, 3166,
3049, 2995, 2950, 2845, 1721, 1656, 1605, 1511, 1437, 1412,
1373, 1280, 1246, 1185, 1108, 1071, 1036, 976, 931, 871, 838,
8167, 735, 707 cmÀ1; ESI-FT-MS: m/z=637.2550, calcd. for
(C37H36N2O8 +H)+: 637.255. Enantiomeric ratio: 87:13, de-
termined by HPLC (Daicel Chirapak OD-H, hexane/2-prop-
anol=85/15, flow rate 1.0 mLminÀ1, T=308C, 254 nm): tR =
14.164 min (major), tR =17.111 min (minor).
(C33H30F2N2O4 +H)+: 557.2252. Enantiomeric ratio: 89:11,
determined by HPLC (Daicel Chirapak AD-H, hexane/2-
propanol=80/20, flow rate 1.0 mLminÀ1, T=308C, 254 nm):
tR =6.381 min (major), tR =24.121 min (minor).
A
2,6-bis(4-chlorophenyl)-1-(4-methoxy-
phenyl)-4-(4-methoxyphenylamino)-1,2,5,6-tetrahydropyri-
dine-3-carboxylate (5aac): Flash column chromatography
eluent, petroleum ether/ethyl acetate=23/1; reaction time=
84 h; yield: 29.3 mg (50%); 77:23 dr; white solid; mp 206–
2088C; [a]2D0: +31.4 (c 0.2, CHCl3). 1H NMR (CDCl3,
400 MHz): d=10.10 (s, 1H), 7.26–7.21 (m, 6H), 7.05 (d, J=
8.4 Hz, 2H), 6.69–6.65 (m, 4H), 6.39–6.33 (m, 4H), 6.21 (s,
1H), 5.00–4.96 (m, 1H), 3.88 (s, 3H), 3.77 (s, 3H), 3.67 (s,
3H), 2.73 (dd, J=15.3, 5.6 Hz, 1H), 2.62 (dd, J=15.3,
3.1 Hz, 1H); 13C NMR (CDCl3, 100 MHz): d=168.4, 158.0,
156.6, 151.4, 142.6, 141.4, 140.9, 132.7, 132.0, 130.4, 128.7,
128.2, 128.2, 127.9, 127.7, 114.6, 114.5, 114.1, 96.5, 57.3, 55.6,
55.5, 55.4, 51.0, 33.6; IR (KBr): n=3362, 3244, 3168, 3047,
2993, 2922, 2850, 1726, 1656, 1603, 1510, 1487, 1459, 1405,
AHCTUNGTREG(NNNU 2R,6S)-Methyl 1-(4-methoxyphenyl)-4-(4-methoxyphen-
ylamino)-2,6-bis(3-nitrophenyl)-1,2,5,6-tetrahydropyridine-3-
carboxylate (5aag): Flash column chromatography eluent,
petroleum ether/ethyl acetate=7/1; reaction time=84 h;
yield: 36.5 mg (60%); 76:24 dr (inseparable diastereomers);
yellow solid; mp 98–1008C. 1H NMR (CDCl3, 400 MHz):
d=10.56 (s, 0.3H), 10.16 (s, 1H), 8.28–8.27 (m, 0.3H), 8.17–
8.16 (m, 1H), 8.12–8.07 (m, 3H), 7.95–7.94 (m, 1H), 7.76 (d,
J=7.7 Hz, 0.3H), 7.62 (d, J=7.7 Hz, 1H), 7.56 (d, J=
7.8 Hz, 0.3H), 7.50 (d, J=7.9 Hz, 0.3H), 7.47–7.42 (m, 3H),
7.32 (t, J=7.9 Hz, 0.3H), 7.03–7.01 (m, 1H), 6.87–6.84 (m,
1H), 6.76–6.72 (m, 1.5H), 6.68–6.62 (m, 5H), 6.41–6.35 (m,
4H), 6.31 (s, 1H), 5.59 (s, 0.3H), 5.18 (t, J=4.3 Hz, 1H),
4.56 (dd, J=11.0, 3.4 Hz, 0.3H), 3.92 (s, 3H), 3.78 (s, 1H),
3.75 (s, 3H), 3.74 (s, 1H), 3.67 (s, 3H), 3.64 (s, 1H), 2.82–
2.72 (m, 2H), 2.70–2.54 (m, 0.8H); 13C NMR (CDCl3,
100 MHz): d=168.6, 168.2, 168.1, 158.3, 157.8, 157.0, 156.1,
1371, 1245, 1183, 1070, 1037, 1012, 979, 888, 812, 736 cmÀ1
;
ESI-FT-MS: m/z=589.1657, calcd. for (C33H30Cl2N2O4 +
H)+: 589.1661. Enantiomeric ratio: 90:10, determined by
HPLC (Daicel Chirapak AD-H, hexane/2-propanol=70/30,
flow rate 1.0 mLminÀ1, T=308C, 254 nm): tR =6.037 min
(major), tR =14.435 min (minor).
A
2,6-bis(4-cyanophenyl)-1-(4-methoxy-
phenyl)-4-(4-methoxyphenylamino)-1,2,5,6-tetrahydropyri-
dine-3-carboxylate (5aad): Flash column chromatography
eluent, petroleum ether/ethyl acetate=6/1; reaction time=
84 h; yield: 62.8 mg (63%); 76:24 dr (inseparable diastereo-
mers); yellow solid; mp 123–1258C. 1H NMR (CDCl3,
400 MHz): d=10.51 (s, 0.3H), 10.11 (s, 1H), 7.63–7.62 (m,
14
asc.wiley-vch.de
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 0000, 000, 0 – 0
ÝÝ
These are not the final page numbers!

Catalytic Asymmetric Five-Component Tandem Reaction
155.2, 152.2, 148.9, 148.5, 148.3, 146.4, 144.8, 144.7, 143.4,
140.1, 139.9, 134.2, 133.4, 132.8, 130.8, 129.9, 129.5, 129.4,
129.1, 128.9, 127.6, 126.7, 123.0, 122.6, 122.5, 122.3, 121.7,
121.7, 121.6, 116.4, 115.3, 114.8, 114.8, 114.8, 114.6, 114.2,
95.6, 95.0, 94.6, 77.3, 77.2, 77.0, 76.7, 64.2, 61.7, 56.9, 56.3,
55.7, 55.7, 55.5, 55.4, 55.3, 55.3, 51.2, 51.0, 50.8, 36.2, 36.0,
33.7; IR (KBr): n=3359, 3243, 3166, 3067, 2998, 2925, 2851,
1725, 1658, 1607, 1512, 1460, 1348, 1245, 1185, 1129, 1072,
1035, 985, 946, 908, 809, 735 cmÀ1; ESI-FT-MS: m/z=
611.2139, calcd. for (C33H30N4O8 +H)+: 611.2142. Enantio-
meric ratio: 84:16, determined by HPLC (Daicel Chirapak
AD-H, hexane/2-propanol=70/30, flow rate 1.0 mLminÀ1,
T=308C, 254 nm): tR =10.436 min (major), tR =33.810 min
(minor).
10.06 (s, 1H), 7.18–7.11 (m, 3H), 7.06 (d, J=7.6 Hz, 2H),
7.01 (d, J=7.3 Hz, 1H), 6.97–6.94 (m, 2H), 6.67–6.60 (m,
4H), 6.46–6.42 (m, 2H), 6.29 (s, 1H), 6.21–6.17 (m, 2H),
5.01–5.00 (m, 1H), 3.91 (s, 3H), 3.75 (s, 3H), 3.66 (s, 3H),
2.80 (dd, J=15.1, 5.8 Hz, 1H), 2.61 (dd, J=15.1, 2.7 Hz,
1H), 2.32 (s, 6H); 13C NMR (CDCl3, 100 MHz): d=168.6,
157.8, 157.1, 150.8, 144.3, 143.2, 141.7, 138.0, 137.7, 130.7,
128.4, 128.0, 127.9, 127.8, 127.4, 127.1, 127.0, 123.8, 123.7,
114.4, 114.0, 113.8, 97.0, 58.2, 55.7, 55.7, 55.3, 50.8, 33.6, 21.8,
21.5; IR (KBr): n=3244, 3168, 3043, 2993, 2921, 2852, 1730,
1653, 1605, 1511, 1459, 1371, 1243, 1183, 1071, 1037, 838,
810, 778, 735 cmÀ1; ESI-FT-MS: m/z=549.2749, calcd. for
(C35H36N2O4 +H)+: 549.2753. Enantiomeric ratio: 90:10, de-
termined by HPLC (Daicel Chirapak IA, hexane/2-propa-
nol=70/30, flow rate 1.0 mLminÀ1, T=308C, 254 nm): tR =
4.569 min (major), tR =6.521 min (minor).
ACHTUNGTRENNUNG(2R,6S)-Methyl 1-(4-methoxyphenyl)-4-(4-methoxyphen-
ylamino)-2,6-diphenyl-1,2,5,6-tetrahydropyridine-3-carboxyl-
ate (5aah): Flash column chromatography eluent, petroleum
ether/ethyl acetate=23/1; reaction time=84 h; yield: 24 mg
(46%); 78:22 dr; yellow solid; mp 228–2298C; [a]2D0: +103.5
(c 0.1, CHCl3). 1H NMR (CDCl3, 400 MHz): d=10.09 (s,
1H), 7.29–7.25 (m, 6H), 7.17–7.15 (m, 4H), 6.66–6.59 (m,
4H), 6.44–6.42 (m, 2H), 6.33 (s, 1H), 6.21–6.18 (m, 2H),
5.05–5.04 (m, 1H), 3.90 (s, 3H), 3.74 (s, 3H), 3.65 (s, 3H),
2.79 (dd, J=15.2, 5.8 Hz, 1H), 2.63 (dd, J=15.2, 2.7 Hz,
1H); 13C NMR (CDCl3, 100 MHz): d=168.6, 157.8, 157.0,
150.9, 144.2, 143.2, 141.5, 130.6, 128.6, 128.1, 127.8, 127.0,
126.7, 126.5, 126.2, 114.5, 114.0, 113.9, 97.0, 58.2, 55.7, 55.6,
55.3, 50.8, 33.5; IR (KBr): n=3244, 3057, 3028, 2996, 2922,
2851, 1736, 1653, 1597, 1508, 1455, 1374, 1319, 1245, 1178,
1106, 1070, 1034, 980, 833, 808, 746 cmÀ1; ESI-FT-MS: m/z=
521.2437, calcd. for (C33H32N2O4 +H)+:521.244. Enantiomer-
ic ratio: 89:11, determined by HPLC (Daicel Chirapak AD-
H, hexane/2-propanol=70/30, flow rate 1.0 mLminÀ1, T=
308C, 254 nm): tR =6.405 min (major), tR =29.936 min
(minor).
A
2,6-bis(4-methoxyphenyl)-1-phenyl-4-
(phenylamino)-1,2,5,6-tetrahydropyridine-3-carboxylate
(5fak): Flash column chromatography eluent, petroleum
ether/ethyl acetate=20/1; reaction time=84 h; yield:
19.8 mg (38%); 86:14 dr; white solid; mp 163–1658C; [a]2D0:
+102.6 (c 0.1, CHCl3). 1H NMR (CDCl3, 400 MHz): d=
10.26 (s, 1H), 7.21 (d, J=8.5 Hz, 2H), 7.14–7.04 (m, 7H),
6.81 (dd, J=8.7, 1.2 Hz, 4H), 6.60 (t, J=7.2 Hz, 1H), 6.52
(d, J=8.1 Hz, 2H), 6.37–6.35 (m, 3H), 5.08–5.07 (m, 1H),
3.92 (s, 3H), 3.79 (s, 3H), 3.78 (s, 3H), 2.85 (dd, J=15.0,
5.5 Hz, 1H), 2.75 (dd, J=15.0, 2.5 Hz, 1H); 13C NMR
(CDCl3, 100 MHz): d=168.6, 158.7, 158.0, 156.3, 147.0,
137.9, 135.8, 134.6, 128.8, 128.8, 127.7, 127.5, 125.8, 125.6,
116.0, 114.0, 113.5, 112.9, 98.1, 57.5, 55.3, 55.2, 54.5, 50.9,
33.7; IR (KBr): n=3244, 3058, 3031, 2997, 2949, 2850, 1732,
1654, 1593, 1503, 1447, 1373, 1323, 1249, 1174, 1110, 1071,
1033, 981, 951, 852, 828, 793, 746, 694 cmÀ1; ESI-FT-MS:
m/z=521.2441, calcd. for (C33H32N2O4 +H)+: 521.244. Enan-
tiomeric ratio: 90:10, determined by HPLC (Daicel Chira-
ACHTUNGTRENNUNG(2R,6S)-Methyl 1-(4-methoxyphenyl)-4-(4-methoxyphen-
pak
AD-H,
hexane/2-propanol=70/30,
flow
rate
ylamino)-2,6-di-p-tolyl-1,2,5,6-tetrahydropyridine-3-carbox-
ylate (5aai): Flash column chromatography eluent, petrole-
um ether/ethyl acetate=21/1; reaction time=84 h; yield:
28.1 mg (51%); 82:18 dr; yellow solid; mp 197–1988C; [a]2D0:
1.0 mLminÀ1, T=308C, 254 nm): tR =5.124 min (major), tR =
14.636 min (minor).
AHCTUNGTRENNUNG
1
+80.9 (c 0.1, CHCl3). H NMR (CDCl3, 400 MHz): d=10.09
column chromatography eluent, petroleum ether/ethyl ace-
tate=70/1; reaction time=84 h; yield: 33.3 mg (68%); 86:14
dr (inseparable diastereomers); yellow solid; mp 183–
1858C; 1H NMR (CDCl3, 400 MHz): d=10.54 (s, 0.2H),
10.17 (s, 1H), 7.44 (d, J=7.7 Hz, 0.4H), 7.22–7.18 (m, 1H),
7.15–7.10 (m, 3H), 7.06–6.88 (m, 12H), 6.77 (d, J=8.1 Hz,
0.4H), 6.63 (t, J=7.2 Hz, 0.2H), 6.51 (t, J=7.2 Hz, 1H),
6.45 (d, J=8.1 Hz, 2H), 6.32 (s, 1H), 6.24–6.21 (m, 2H),
6.07 (s, 0.2H), 5.03–5.02 (m, 1H), 4.45 (dd, J=12.6, 3.5 Hz,
0.2H), 3.84 (s, 3H), 3.65 (s, 0.5H), 2.79 (dd, J=15.1, 5.6 Hz,
1H), 2.68 (dd, J=15.1, 2.5 Hz, 1H), 2.43–2.34 (m, 0.3H),
2.31 (s, 0.5H), 2.26 (s, 3H), 2.24 (s, 3H), 2.16 (s, 0.5H);
13C NMR (CDCl3, 100 MHz): d=167.5, 155.2, 146.0, 139.9,
138.6, 136.9, 135.5, 134.7, 128.2, 127.9, 127.8, 127.7, 125.5,
125.2, 124.7, 124.5, 114.9, 111.8, 97.1, 56.8, 53.9, 49.9, 32.6,
20.0, 19.9; IR (KBr): n=3244, 3170, 3089, 3024, 2922, 2854,
1729, 1656, 1594, 1500, 1444, 1372, 1319, 1255, 1186, 1119,
1073, 1037, 982, 950, 924, 852, 813, 788, 743, 695 cmÀ1; ESI-
FT-MS: m/z=489.2534, calcd. for (C33H32N2O2 +H)+:
489.2542. Enantiomeric ratio: 86:14, determined by HPLC
(Daicel Chirapak IA, hexane/2-propanol=85/15, flow rate
(s, 1H), 7.17 (d, J=8.0 Hz, 2H), 7.09–7.03 (m, 6H), 6.67–
6.59 (m, 4H), 6.45–6.43 (m, 2H), 6.27 (s, 1H), 6.22 (d, J=
8.7 Hz, 2H), 5.01–5.00 (m, 1H), 3.89 (s, 3H), 3.75 (s, 3H),
3.66 (s, 3H), 2.78 (dd, J=15.1, 5.7 Hz, 1H), 2.63 (d, J=15.1,
2.8 Hz, 1H), 2.34 (s, 3H), 2.32 (s, 3H); 13C NMR (CDCl3,
100 MHz): d=168.7, 157.7, 157.0, 150.8, 141.7, 141.29, 140.1,
136.5, 135.6, 130.8, 129.2, 128.8, 127.8, 126.7, 126.4, 114.5,
114.0, 113.9, 97.1, 57.9, 55.7, 55.5, 55.4, 50.8, 33.6, 21.1, 21.0;
IR (KBr): n=3366, 3248, 3045, 2922, 2851, 1729, 1654, 1606,
1510, 1458, 1411, 1372, 1245, 1182, 1108, 1070, 1036, 980,
928, 810, 736 cmÀ1; ESI-FT-MS: m/z=549.2751, calcd. for
(C35H36N2O4 +H)+: 549.2753. Enantiomeric ratio: 87:13, de-
termined by HPLC (Daicel Chirapak IA, hexane/2-propa-
nol=85/15, flow rate 1.0 mLminÀ1, T=308C, 254 nm): tR =
8.004 min (major), tR =18.534 min (minor).
ACHTUNGTRENNUNG(2R,6S)-Methyl 1-(4-methoxyphenyl)-4-(4-methoxyphen-
ylamino)-2,6-di-m-tolyl-1,2,5,6-tetrahydropyridine-3-carbox-
ylate (5aaj): Flash column chromatography eluent, petrole-
um ether/ethyl acetate=23/1; reaction time=84 h; yield:
23.1 mg (42%); 81:19 dr; yellow solid; mp 189–1918C; [a]2D0:
+115.3 (c 0.2, CHCl3). 1H NMR (CDCl3, 400 MHz): d=
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FULL PAPERS
1.0 mLminÀ1, T=308C, 254 nm): tR =5.888 min (major), tR =
9.910 min (minor).
ACHTUNGTRENNUNG(2R,6S)-Methyl 2,6-bis(3,4-difluorophenyl)-1-(4-methoxy-
1176, 1029, 953, 880, 797, 734, 706, 669 cmÀ1; ESI-FT-MS:
m/z=691.0808, calcd. for (C34H32Br2N2O4 +H)+: 691.0807.
Enantiomeric ratio: 84:16, determined by HPLC (Daicel
Chirapak AD-H, hexane/2-propanol=70/30, flow rate
1.0 mLminÀ1, T=308C, 254 nm): tR =5.988 min (major), tR =
18.179 min (minor).
phenyl)-4-(4-methoxyphenylamino)-1,2,5,6-tetrahydropyri-
dine-3-carboxylate (5aaf): Flash column chromatography
eluent, petroleum ether/ethyl acetate=18/1; reaction time=
84 h; yield: 38.4 mg (65%); 67:33 dr; white solid; mp 142–
1438C; [a]2D0: +15.3 (c 0.3, CHCl3). 1H NMR (CDCl3,
400 MHz): d=10.14 (s, 1H), 7.11–6.99 (m, 3H), 6.96–6.88
(m, 2H), 6.85–6.82 (m, 1H), 6.72–6.65 (m, 4H), 6.43–6.37
(m, 4H), 6.17 (s, 1H), 4.96–4.94 (m, 1H), 3.89 (s, 3H), 3.77
(s, 3H), 3.68 (s, 3H), 2.73 (dd, J=15.4, 5.5 Hz, 1H), 2.64
(dd, J=15.4, 3.2 Hz, 1H); 13C NMR (CDCl3, 100 MHz): d=
168.2, 157.6 (J=110.4 Hz), 151.7, 140.5, 140.4 (J=130.2 Hz),
130.3, 127.7, 117.1 (J=17.1 Hz), 115.7 (J=17.4 Hz), 114.7,
114.6, 114.2, 96.0, 56.8, 55.6, 55.4, 51.1, 33.5; IR (KBr): n=
3243, 3169, 3050, 2994, 2918, 2845, 1730, 1656, 1607, 1511,
1455, 1430, 1370, 1275, 1186, 1106, 1070, 1037, 986, 934, 883,
800, 776, 737 cmÀ1; ESI-FT-MS: m/z=593.2049, calcd. for
(C33H28F4N2O4 +H)+: 593.2063. Enantiomeric ratio: 84:16,
determined by HPLC (Daicel Chirapak AD-H, hexane/2-
propanol=70/30, flow rate 1.0 mLminÀ1, T=308C, 254 nm):
tR =5.439 min (major), tR =10.193 min (minor).
AHCTUNGTREG(NNUN 2R,6S)-Allyl 2,6-bis(4-bromophenyl)-1-(4-methoxyphen-
yl)-4-(4-methoxyphenylamino)-1,2,5,6-tetrahydropyridine-3-
carboxylate (5aca): Flash column chromatography eluent,
petroleum ether/ethyl acetate=18/1; reaction time=84 h;
yield: 41.6 mg (59%); 77:23 dr; white solid; mp 83–858C;
1
[a]2D0: +32.4 (c 0.4, CHCl3). H NMR (CDCl3, 400 MHz): d=
10.13 (s, 1H), 7.40–7.36 (m, 4H), 7.17 (d, J=8.3 Hz, 2H),
7.00 (d, J=8.4 Hz, 2H), 6.70–6.65 (m, 4H), 6.39–6.35 (m,
4H), 6.23 (s, 1H), 6.10–6.03 (m, 1H), 5.42–5.28 (m, 2H),
5.00–4.95 (m, 1H), 4.83–4.77 (m, 2H), 3.77 (s, 3H), 3.67 (s,
3H), 2.74 (dd, J=15.3, 5.6 Hz, 1H), 2.63 (dd, J=15.4,
3.1 Hz, 1H); 13C NMR (CDCl3, 100 MHz): d=167.5, 158.0,
156.9, 151.5, 143.1, 141.9, 140.9, 133.0, 131.6, 131.2, 130.4,
128.6, 128.3, 127.7, 120.8, 120.1, 117.7, 114.6, 114.6, 114.1,
96.3, 64.4, 57.3, 55.6, 55.6, 55.4, 33.7; IR (KBr): n=3364,
3243, 3165, 3047, 2959, 2924, 2853, 1729, 1653, 1603, 1510,
1483, 1460, 1403, 1370, 1242, 1176, 1065, 1036, 980, 937, 799,
A
738, 702 cmÀ1
; ESI-FT-MS: m/z=703.0796, calcd. for
ylamino)-2,6-di(thiophen-2-yl)-1,2,5,6-tetrahydropyridine-3-
carboxylate (5aal): Flash column chromatography eluent,
petroleum ether/ethyl acetate=20/1; reaction time=84 h;
yield: 20.0 mg (38%); 76:24 dr (inseparable diastereomers);
yellow solid; mp 226–2288C. 1H NMR (CDCl3, 400 MHz):
d=10.42 (s, 0.3H), 10.28 (s, 1H), 7.23 (d, J=5.1 Hz, 0.4H),
7.13–7.11 (m, 2H), 7.07 (dd, J=5.0, 1.1 Hz, 0.4H), 7.02–7.00
(m, 0.4H), 6.96–6.91 (m, 1.5H), 6.89–6.72 (m, 11.6H), 6.68–
6.55 (m, 2H), 6.25 (s, 1H), 5.94 (s, 0.3H), 5.25 (t, J=4.5 Hz,
1H), 4.78 (t, J=7.7 Hz, 0.3H), 3.86 (s, 3H), 3.78 (s, 1H),
3.77 (s, 3H), 3.74 (s, 1H), 3.71 (s, 1H), 3.69 (s, 3H), 2.97
(dd, J=15.6, 5.2 Hz, 1H), 2.80–2.75 (m, 1.6H); 13C NMR
(CDCl3, 100 MHz): d=168.2, 157.8, 156.7, 153.8, 152.0,
149.6, 147.5, 130.8, 127.7, 126.4, 126.3, 126.1, 124.1, 123.4,
119.0, 115.8, 114.2, 114.1, 96.1, 55.5, 55.4, 53.5, 50.8, 34.0,
29.7; IR (KBr): n=3247, 3173, 3103, 3068, 2922, 2851, 1727,
1657, 1607, 1510, 1460, 1379, 1244, 1184, 1106, 1068, 1035,
973, 801, 702 cmÀ1; ESI-FT-MS: m/z=533.1568, calcd. for
(C29H28N2O4S2 +H)+: 533.1569. Enantiomeric ratio: 87:13,
determined by HPLC (Daicel Chirapak IC, hexane/2-propa-
nol=80/20, flow rate 1.0 mLminÀ1, T=308C, 254 nm): tR =
7.304 min (major), tR =8.573 min (minor).
(C35H32Br2N2O4 +H)+: 703.0807. Enantiomeric ratio: 90:10,
determined by HPLC (Daicel Chirapak AD-H, hexane/2-
propanol=85/15, flow rate 1.0 mLminÀ1, T=308C, 254 nm):
tR =8.659 min (major), tR =26.563 min (minor).
AHCTUNGTREG(NNUN 2R,6S)-Isopropyl 2,6-bis(4-bromophenyl)-1-(4-methoxy-
phenyl)-4-(4-methoxyphenylamino)-1,2,5,6-tetrahydropyri-
dine-3-carboxylate (5ada): Flash column chromatography
eluent, petroleum ether/ethyl acetate=18/1; reaction time=
84 h; yield: 56.4 mg (80%); 80:20 dr; white solid; mp 184–
1868C; [a]2D0: +26.2 (c 0.5, CHCl3). 1H NMR (CDCl3,
400 MHz): d=10.19 (s, 1H), 7.38 (d, J=8.0 Hz, 4H), 7.17
(d, J=8.3 Hz, 2H), 6.99 (d, J=8.4 Hz, 2H), 6.70–6.66 (m,
4H), 6.40–6.37 (m, 4H), 6.16 (s, 1H), 5.25–5.19 (m, 1H),
4.95–4.93 (m, 1H), 3.77 (s, 3H), 3.68 (s, 3H), 2.72 (dd, J=
15.4, 5.5 Hz, 1H), 2.62 (dd, J=15.4, 3.3 Hz, 1H), 1.37 (dd,
J=6.2, 4.3 Hz, 6H); 13C NMR (CDCl3, 100 MHz): d=167.6,
157.9, 156.2, 151.5, 143.3, 141.9, 141.0, 131.6, 131.1, 130.6,
128.6, 128.4, 127.6, 120.8, 120.1, 114.9, 114.5, 114.1, 96.9,
66.9, 57.3, 55.9, 55.6, 55.4, 33.7, 22.4, 22.2; IR (KBr): n=
3444, 3244, 3049, 2958, 2924, 2853, 1733, 1648, 1605, 1511,
1483, 1459, 1401, 1372, 1243, 1176, 1105, 1063, 1036, 957,
891, 804 cmÀ1; ESI-FT-MS: m/z=705.0958, exact mass calcd.
for (C35H34Br2N2O4 +H)+: 705.0964. Enantiomeric ratio:
87:13, determined by HPLC (Daicel Chirapak IA, hexane/2-
propanol=70/30, flow rate 1.0 mLminÀ1, T=308C, 254 nm):
tR =5.206 min (major), tR =19.283 min (minor).
ACHTUNGTRENNUNG(2R,6S)-Ethyl 2,6-bis(4-bromophenyl)-1-(4-methoxyphen-
yl)-4-(4-methoxyphenylamino)-1,2,5,6-tetrahydropyridine-3-
carboxylate (5aba): Flash column chromatography eluent,
petroleum ether/ethyl acetate=18/1; reaction time=84 h;
yield: 44.3 mg (64%); 88:12 dr; white solid; mp 177–1798C;
AHCTUNGTREG(NNUN 2R,6S)-tert-Butyl 2,6-bis(4-bromophenyl)-1-(4-methoxy-
1
[a]2D0: +23.0 (c 0.2, CHCl3). H NMR (CDCl3, 400 MHz): d=
phenyl)-4-(4-methoxyphenylamino)-1,2,5,6-tetrahydropyri-
dine-3-carboxylate (5aea): Flash column chromatography
eluent, petroleum ether/ethyl acetate=24/1; reaction time=
84 h; yield: 36.0 mg (50%); 90:10 dr (inseparable diastereo-
mers); yellow solid; mp 100–1028C. 1H NMR (CDCl3,
400 MHz): d=10.47 (s, 0.1H), 10.14 (s, 1H), 7.44–7.42 (m,
0.3H), 7.40–7.37 (m, 4H), 7.32–7.28 (m, 0.5H), 7.17 (d, J=
8.3 Hz, 2H), 7.08 (d, J=8.5 Hz, 0.3H), 7.00 (d, J=8.4 Hz,
2H), 6.97–6.95 (m, 0.3H), 6.83–6.81 (m, 0.3H), 6.69–6.65
(m, 5H), 6.40–6.37 (m, 4H), 6.11 (s, 1H), 5.50 (s, 0.1H),
4.91–4.89 (m, 1H), 4.37 (dd, J=11.7, 3.3 Hz, 0.1H), 3.77 (s,
10.13 (s, 1H), 7.40–7.37 (m, 4H), 7.16 (d, J=8.2 Hz, 2H),
7.00 (d, J=8.4 Hz, 2H), 6.69–6.65 (m, 4H), 6.39–6.34 (m,
4H), 6.19 (s, 1H), 4.96–4.94 (s, 1H), 4.42–4.38 (m, 1H),
4.31–4.26 (m, 1H), 3.77 (s, 3H), 3.67 (s, 3H), 2.72 (dd, J=
15.3, 5.6 Hz, 1H), 2.62 (dd, J=15.4, 3.1 Hz, 1H), 1.40 (t, J=
7.1 Hz, 3H); 13C NMR (CDCl3, 100 MHz): d=168.0, 157.9,
156.4, 151.5, 143.2, 141.9, 140.9, 131.6, 131.2, 130.5, 128.6,
128.3, 127.7, 120.8, 120.1, 114.6, 114.6, 114.1, 96.6, 59.6, 57.3,
55.7, 55.6, 55.4, 33.6, 14.7; IR (KBr): n=3438, 2972, 2919,
2854, 1652, 1610, 1511, 1483, 1438, 1406, 1371, 1315, 1244,
16
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Catalytic Asymmetric Five-Component Tandem Reaction
0.4H), 3.77 (s, 3H), 3.69 (s, 0.4H), 3.68 (s, 3H), 2.69 (dd, J=
15.4, 5.4 Hz, 1H), 2.60 (dd, J=15.4, 3.6 Hz, 1H), 1.59 (s,
9H), 1.39 (s, 1H); 13C NMR (CDCl3, 100 MHz): d=168.0,
157.7, 155.6, 151.6, 143.3, 142.0, 141.0, 131.5, 131.1, 130.8,
128.7, 128.5, 128.4, 127.6, 120.7, 120.0, 115.3, 114.5, 114.0,
97.9, 80.0, 57.2, 56.5, 55.6, 55.4, 33.6, 28.7, 28.4; IR (KBr):
n=3360, 3247, 3046, 2966, 2928, 2835, 1726, 1648, 1605,
1510, 1483, 1456, 1400, 1366, 1245, 1156, 1106, 1066, 1037,
1101, 953, 898, 810, 737 cmÀ1; ESI-FT-MS: m/z=719.1113,
calcd. for (C36H36Br2N2O4 +H)+: 719.112. Enantiomeric
ratio: 95:5, determined by HPLC (Daicel Chirapak IA,
hexane/2-propanol=95/5, flow rate 1.0 mLminÀ1, T=308C,
254 nm): tR =5.065 min (major), tR =10.266 min (minor).
0.5 mL) was added. After being stirred at 358C for 84 h, the
reaction mixture was filtered to remove molecular sieves
and the solid powder was washed with ethyl acetate. The re-
sultant solution was concentrated under the reduced pres-
sure to give the residue, which was purified through flash
column chromatography on silica gel to afford pure product
5aaa.
Procedure for the Synthesis of Intermediate 7 via
stepwise Procedures at 358C (Scheme 5)
After a solution of 4-methoxyaniline 1a (0.1 mmol), methyl
acetoacetate 2a (0.1 mmol), the catalyst 4f (0.015 mmol),
and 3ꢂ molecular sieves (100 mg) in toluene (1 mL) had
been stirred at 358C for 12 h, the reaction mixture was fil-
tered to remove molecular sieves and the solid powder was
washed with ethyl acetate. The resultant solution was con-
centrated under the reduced pressure to give the residue,
which was purified through flash column chromatography
on silica gel to afford the intermediate 6. Then, the solution
of intermediate 6 (0.1 mmol) in toluene (0.5 mL) was added
to the mixture of 4-bromobenzaldehyde 3a (0.1 mmol), the
catalyst 4f (0.015 mmol), 3ꢂ molecular sieves (100 mg) in
toluene (0.5 mL). After stirring at 358C for 24 h, TLC of the
reaction mixture indicated that a trace of intermediate 7
had been generated.
A
2,6-bis(4-bromophenyl)-1-(4-methoxy-
phenyl)-4-(4-methoxyphenylamino)-1,2,5,6-tetrahydropyri-
dine-3-carboxylate (5afa): Flash column chromatography
eluent, petroleum ether/ethyl acetate=6/1; reaction time=
84 h; yield: 48.6 mg (64%); 76:24 dr; white solid; mp 105–
1088C; [a]2D0: +39.3 (c 0.4, CHCl3); 1H NMR (CDCl3,
400 MHz): d=10.18 (s, 1H), 7.40–7.30 (m, 7H), 7.32 (d, J=
8.5 Hz, 2H), 7.09 (d, J=8.3 Hz, 2H), 6.99 (d, J=8.4 Hz,
2H), 6.71–6.64 (m, 4H), 6.40–6.36 (m, 4H), 6.21 (s, 1H),
5.46 (d, J=12.5 Hz, 1H), 5.22 (d, J=12.5 Hz, 1H), 4.94–4.92
(m, 1H), 3.77 (s, 3H), 3.67 (s, 3H), 2.72 (dd, J=15.5, 5.4 Hz,
1H), 2.63 (dd, J=15.5, 3.5 Hz, 1H); 13C NMR (CDCl3,
100 MHz): d=167.6, 158.0, 157.0, 151.7, 143.0, 141.8, 140.9,
136.8, 131.6, 131.1, 130.4, 128.8, 128.6, 128.4, 128.1, 127.9,
127.7, 120.8, 120.1, 115.2, 114.5, 114.1, 96.1, 65.3, 57.1, 56.1,
55.6, 55.4, 33.7; IR (KBr): n=3361, 3251, 3062, 2955, 2925,
2853, 1728, 1651, 1603, 1510, 1484, 1455, 1403, 1370, 1241,
1175, 1105, 1063, 1036, 809, 737, 699 cmÀ1; ESI-FT-MS:
m/z=753.0966, calcd. for (C39H34Br2N2O4 +H)+:753.0964.
Enantiomeric ratio: 88:12, determined by HPLC (Daicel
Chirapak AD-H, hexane/2-propanol=70/30, flow rate
1.0 mLminÀ1, T=308C, 254 nm): tR =6.696 min (major), tR =
19.372 min (minor).
Procedure for the Synthesis of Intermediate 7 via
Stepwise Procedures at 908C (Scheme 6)
After a solution of 4-methoxyaniline 1a (5 mmol), methyl
acetoacetate 2a (5 mmol), benzoic acid (0.5 mmol), and 3ꢂ
molecular sieves (1.5 g) in toluene (20 mL) had been stirred
at 908C for 24 h, the reaction mixture was filtered to
remove molecular sieves and the solid powder was washed
with ethyl acetate. The resultant solution was concentrated
under the reduced pressure to give the residue, which was
purified through flash column chromatography on silica gel
to afford the intermediate 6. Then, the solution of inter-
mediate 6 (3 mmol) in toluene (2 mL) was added to the mix-
ture of 4-bromobenzaldehyde 3a (3 mmol), benzoic acid
(0.6 mmol), piperidine (0.6 mmol), 3ꢂ molecular sieves
(1.5 g) in toluene (3 mL). After stirred at 908C for 24 h, the
reaction mixture was filtered to remove molecular sieves
and the solid powder was washed with ethyl acetate. The re-
sultant solution was concentrated under the reduced pres-
sure to give the residue, which was purified through flash
column chromatography on silica gel to afford the inter-
mediate 7.
Procedure for the Asymmetric Five-Component
Reaction to Isolate Intermediate 7 (Scheme 3)
After a solution of 4-methoxyaniline 1a (0.2 mmol), methyl
acetoacetate 2a (0.1 mmol), the catalyst 4f (0.01 mmol), and
4ꢂ molecular sieves (100 mg) in 1,4-dioxane (0.5 mL) had
been stirred at 358C for 30 min, the solution of 4-bromoben-
zaldehyde 3a (0.2 mmol) in 1,4-dioxane (0.5 mL) was added.
After being stirred at 358C for 48 h, the reaction mixture
was filtered to remove molecular sieves and the solid
powder was washed with ethyl acetate. The resultant solu-
tion was concentrated under the reduced pressure to give
the residue, which was purified through flash column chro-
matography on silica gel to afford pure product 5aaa and in-
termediates 7 and 8.
Procedure for the Synthesis of Intermediate 7 via the
One-Pot Protocol (Scheme 7)
After a solution of 4-methoxyaniline 1a (1 mmol), methyl
acetoacetate 2a (1 mmol), 4-bromobenzaldehyde 3a
(1 mmol), racemic phosphoric acid 4k (0.2 mmol), and 3ꢂ
molecular sieves (600 mg) in 1,4-dioxane (4 mL) had been
stirred at 508C for 24 h, the reaction mixture was filtered to
remove molecular sieves and the solid powder was washed
with ethyl acetate. The resultant solution was concentrated
under the reduced pressure to give the residue, which was
purified through flash column chromatography on silica gel
to afford the intermediate 7.
Procedure for the Asymmetric Reaction of
Intermediate 7 and in situ Formed Imine (Scheme 4)
After a solution of 4-methoxyaniline 1a (0.1 mmol), 4-bro-
mobenzaldehyde
3a
(0.1 mmol),
the
catalyst
4f
(0.015 mmol), and 3ꢂ molecular sieves (100 mg) in the
mixed toluene/1,4-dioxane (1:1 v/v, 0.5 mL) had been stirred
at 358C for 30 min, the solution of the intermediate 7
(0.1 mmol) in the mixed toluene/1,4-dioxane (1:1 v/v,
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Feng Shi et al.
FULL PAPERS
(Z)-Methyl 3-(4-methoxyphenylamino)but-2-enoate (6):
[6] a) J. F. Hayes, M. Shipman, H. Twin, Chem. Commun.
2001, 1784–1785; b) T. Urushima, D. Sakamoto, H. Ishi-
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Flash column chromatography eluent, petroleum ether/ethyl
1
acetate=30/1; colorless liquid. H NMR (CDCl3, 400 MHz):
d=10.12 (s, 1H), 7.02 (d, J=8.8 Hz, 2H), 6.85 (d, J=8.8 Hz,
2H), 4.65 (s, 1H), 3.80 (s, 3H), 3.67 (s, 3H), 1.88 (s, 3H);
13C NMR (CDCl3, 100 MHz): d=170.8, 160.1, 157.5, 132.1,
126.8, 114.2, 84.3, 55.4, 50.1, 20.1; IR (KBr): n=3264, 3189,
2996, 2947, 2835, 1654, 1614, 1513, 1490, 1438, 1385, 1357,
1273, 1247, 1164, 1107, 1057, 1034, 1007, 952, 916, 845, 816,
786, 681 cmÀ1
;
ESI-FT-MS: m/z 222.1122, calcd. for
(C12H15NO3 +H)+: 222.113.
(Z)-Methyl 2-(4-bromobenzylidene)-3-(4-methoxyphen-
ylamino)but-3-enoate (7): Flash column chromatography
eluent, petroleum ether/ethyl acetate=40/1; yellow solid;
mp 99–1018C. 1H NMR (CDCl3, 400 MHz): d=10.11 (s,
1H), 7.44 (d, J=8.5 Hz, 2H), 7.21 (d, J=8.4 Hz, 2H), 7.07
(d, J=16.1 Hz, 1H), 7.01–6.98 (m, 2H), 6.87–6.82 (m, 2H),
6.58 (d, J=16.1 Hz, 1H), 5.08 (s, 1H), 3.79 (s, 3H), 3.72 (s,
3H); 13C NMR (CDCl3, 100 MHz): d=170.8, 156.9, 156.8,
134.7, 133.5, 132.4, 132.0, 128.6, 125.1, 123.9, 122.9, 114.3,
83.6, 55.4, 50.5; IR (KBr): n=3269, 2946, 2835, 1731, 1652,
1599, 1511, 1487, 1372, 1272, 1163, 1107, 1044, 1010, 970,
813, 788, 734 cmÀ1; ESI-FT-MS: m/z=388.0537, calcd. for
(C19H18BrNO3 +H)+: 388.0548, found .
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Acknowledgements
We are grateful for financial support from National Natural
Science Foundation of China (21002083 and 21232007) and
PAPD of Jiangsu Higher Education Institutions.
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18
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FULL PAPERS
Catalytic Asymmetric Five-Component Tandem Reaction:
Diastereo- and Enantioselective Synthesis of Densely
Functionalized Tetrahydropyridines with Biological
Importance
19
Adv. Synth. Catal. 2013, 355, 1 – 19
Feng Shi,* Wei Tan, Ren-Yi Zhu, Gui-Juan Xing,
Shu-Jiang Tu*
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
19
ÞÞ
These are not the final page numbers!