Catalytic asymmetric synthesis of both enantiomers of 4-substituted 1,4-Dihydropyridines with the use of bifunctional Thiourea-Ammonium salts bearing different counterions

Article abstract of DOI:10.3390/molecules15118305

Organoammonium salts composed of a Bronsted acid and an anilinothiourea promoted the Michael addition of β-keto esters and α,β-unsaturated aldehydes in the presence of primary amines to give functionalized 1,4-dihydropyridines enantioselectively. With the

Full text of DOI:10.3390/molecules15118305

Molecules 2010, 15, 8305-8326; doi:10.3390/molecules15118305
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Catalytic Asymmetric Synthesis of Both Enantiomers of
4-Substituted 1,4-Dihydropyridines with the Use of Bifunctional
Thiourea-Ammonium Salts Bearing Different Counterions
Kohzo Yoshida, Tsubasa Inokuma, Kiyosei Takasu and Yoshiji Takemoto *
Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501,
Japan
* Author to whom correspondence should be addressed; E-Mail: takemoto@pharm.kyoto-u.ac.jp; Tel.:
+81-75-753-4528; Fax: +81-75-753-4569.
Received: 13 October 2010; in revised form: 8 November 2010 / Accepted: 12 November 2010 /
Published: 15 November 2010
Abstract: Organoammonium salts composed of a Brønsted acid and an anilinothiourea
promoted the Michael addition of β-keto esters and α,β-unsaturated aldehydes in the
presence of primary amines to give functionalized 1,4-dihydropyridines enantioselectively.
With the use of the different Brønsted acids such as DFA and HBF4 with the same
bifunctional thiourea, both enantiomers of 4-substituted 1,4-dihydropyridine were
synthesized from the same starting materials.
Keywords: bifunctional thiourea-ammonium salt; aminothiourea; Brønsted acid;
1,4-dihydropyridines; Michael addition; α,β-unsaturated aldehydes, β-keto esters
1. Introduction
Asymmetric catalysis using bifunctional catalysts has attracted considerable attention in synthetic
organic chemistry. Various types of bifunctional metal- [1-4] and organo-catalysts [5,6] have been
developed and used for catalytic enantioselective reactions over the past decade. Generally, bifunctional
acid-base catalysts concurrently activate both nucleophiles and electrophiles to promote addition
reactions with high catalytic activity and excellent stereoselectivity via a dual activation mechanism
[7,8]. We have previously reported that bifunctional aminothiourea 1 could be used for the asymmetric
1,2- and 1,4-addition of various active methylene compounds to imines and nitroolefins [see (a) in

Molecules 2010, 15
8306
Figure 1)] [9-11]. A different approach to asymmetric organocatalysis has been realized through the use
of conjugated acid systems, such as in Diels-Alder and aldol reactions [12-15]. By combining these two
concepts, we recently realized Brønsted acid-bifunctional thiourea co-catalysis, in which bifunctional
thiourea not only activates an achiral Brønsted acid, but also changes its reaction mode to give the
alternative regioisomer as a major product, albeit with moderate enantioselectivity [16]. Our working
hypothesis is shown in Figure 1, (b) and (c). When thiourea 1 and a Brønsted acid (HX) are mixed in a
1:1 ratio, ammonium salt complexes A and B are equilibrated with the starting materials 1 and HX,
depending on the acidity of HX and the hydrogen-bonding (H-bonding) ability of the conjugate base (X-).
If the conjugate base is a strong H-bonding acceptor, H-bonding complex A, in which X- is anchored to
the thiourea moiety by H-bonds, would be predominant. Otherwise, ion-pair complex B might prevail.
The difference between the original bifunctional thiourea 1 and ammonium salt A is that the conjugate
base (X-) acts not as a nucleophile, but as a base, which activates a co-existing nucleophile (Nu-H) such
as enamino ester or β-keto ester. To explore this hypothesis, a wide range of Brønsted acid-bifunctional
thiourea co-catalysts were synthesized and examined. In this article, we describe the details of the
versatility of various Brønsted acid-bifunctional thiourea co-catalysts [17,18] together with their
application to the asymmetric synthesis of functionalized 1,4-dihydropyridines.
Figure 1. Proposed dual activation mode of aminothiourea.
(a) Dual activation by original aminothiourea 1
S
Ar
S
N
H
N
H
R
R
Nu-H
E
Ar
Nu
E H
N
N
N
H
H
H
E
R
+ 1
N
Nu
R
1
(b) Bifunctional thiourea-ammonium salt
S
S
X
S
Ar
Ar
Ar
N
H
N
N
H
N
N
N
R
X
R
R
H
H
R
H
N
H
N
N
R
1
R
H
H
+
H-X
ion-pair complex B
hydrogen-bond (HB) complex A
(c) Dual activation by thiourea-ammonium salt 2a
S
S
Ar
N
N
H
Ar
R
R
N
H
N
H
Nu-H
E
H
N
R
R
Nu
E H
N
H
X
+ A [1• H-X]
H
X
E
H
A
Nu

Molecules 2010, 15
8307
2. Results and Discussion
1,4-Dihydropyridines (1,4-DHPs) and their derivatives are important bioactive compounds and
versatile synthetic intermediates in the pharmaceutical industry and in process chemistry. Due to the
need for 1,4-DHP derivatives, various synthetic methods have been developed [19-22]. Although
symmetrical 1,4-DHP can be easily prepared by the well-known Hantzsch method [23], new methods
for the synthesis of unsymmetrical DHPs are still needed. Furthermore, there have been only a few
reports on the organocatalytic enantioselective synthesis of 1,4-DHP [24-26]. These routes are shown in
Scheme 1. The highly enantioselective synthesis of 1,4-DHP via route a from cinnamaldehyde,
arylamine, and a 1,3-dicarbonyl compound with a chiral phosphoric acid was achieved by Gong's group
[24]. Similarly, Renaud et al. reported that another chiral phosphoric acid catalyzed three-component
cyclization to afford the product with moderate selectivity (50% ee) via route b [25]. Therefore, we
examined three-component cyclization via both routes a and b in the presence of the Brønsted acid-
bifunctional thiourea co-catalysts to test their abilities in asymmetric reactions.
Scheme 1. Synthetic routes to 1,4-DHPs.
OH
O
O
O
CHO
R2
R3
OR4
R3
OR4
R1
R2
N
O
R1
R2
R2
N
(a)
(b)
H
CO2R4
R3
-H2O
R1 NH2
O
O
N
R1
R1
R1
R3
NH
R2
O
CHO
R3
OR4
R2
NH
R3
OR4
OR
CHO
2.1. Synthesis of chiral bifunctional thioureas 1a-h for Brønsted acid-thiourea co-catalysts
To investigate the catalytic potential of various Brønsted acid-thiourea co-catalysts, we first
synthesized several bifunctional thioureas 1a-h bearing a functional group, such as a hydroxy or N-
arylamino group, which have different Brønsted basicities (Figure 2). By changing the basicity of the
second functional group of the thiourea catalyst as well as the acidity of Brønsted acid, we can tune both
the acidity of the oxonium or ammonium proton and the basicity of the counterion (X−).
To synthesize N-arylaminothioureas 1d-h, we examined two synthetic routes. In the first Buchwald-
type amination of (R,R)-1,2-cyclohexyldiamine with appropriate aryl iodides was used as a key step
(Scheme 2). However, the key reaction gave the desired products 1d and 1e in low yields. We then used
the second route to synthesize more functionalized catalysts 1f-h, which involved the diastereoselective
ring-opening of chiral aziridine 2 [27] with functionalized anilines, as shown in Scheme 3. The ring-
opening of 2 with the corresponding anilines produced the two diastereomers 3f-h and 4f-h. The
absolute configurations of 3f and 4f were determined to be (1S,2S,1S') and (1R,2R,1S'), respectively,
based on the results of an X-ray single crystallographic analysis of 4f. The stereochemistries of other
products 3g-h and 4g-h were deduced from this result for 4f (Scheme 3). The hydrogenation and
thiocarbamoylation of 3f-h provided the desired thioureas 1f-h in good yields.

Molecules 2010, 15
8308
Figure 2. Structures of thiourea catalysts employed.
S
S
S
Ar
Ar
Ar
N
H
N
N
N
N
N
H
H
H
H
H
N
OH
O
OH
1a
1b
1c
S
S
Ar
N
N
Ar
H
H
N
N
HN
H
H
HN
X
X
Y
Y
1f: X = F, Y = OMe
1g: X = Y = OMe
1h: X = F, Y = OiPr
1d: X = Y = H
1e: X = OMe, Y = H
(Ar = 3,5-(CF3)2-C6H3)
Scheme 2. Synthesis of thiourea (R, R)-1d and 1e.
Scheme 3. Synthesis of thiourea (R, R)-1f-h.
R2
R1
Ph
Ph
N
N
H
H
NH2
+
HN
R1
HN
R1
N
cat. B(C6F5)3
Ph
R2
R2
MeCN, 65 ºC, 36 h
2
3f-h
(1S,2S,1'S)-
4f-h
(1R,2R,1'S)-
1
2
3f
R = F, R = MeO ( : 43%, : 17%)
4f
1
2
3g
R = R = MeO ( :52%,
4g
: 25%)
1
2
3h
R = F, R = i-PrO ( : 57%,
4h
:11%)
CF3
CF3
S
Pd/C
F3C
N
N
F3C
NCS
H
H
HCO2NH4
HN
R1
3f-h
(1S,2S,1'S)-
MeOH, 50 ºC, 12 h
DCM, rt, 3 h
R2
1f
(S, S)- (84%)
(S, S)- (72%)
1h
(S, S)- (81%)
1g

Molecules 2010, 15
8309
2.2. Brønsted acid-bifunctional thiourea co-catalysts for the synthesis of 3,4-disubstituted 1,4-DHPs
We initially investigated the reaction of enamino ester 5a and α,β-unsaturated aldehyde 6a in toluene
with Brønsted acid-bifunctional thiourea co-catalysts as well as achiral Brønsted acids. Representative
results are summarized in Table 1. Notably, strong Brønsted acids such as HBF4 and TfOH provided the
desired 1,4-DHP 7aa as a major product, while the same reactions with TFA (trifluoroacetic acid) and
DFA (difluoroacetic acid) afforded mixtures of 1,4-DHP 7aa and 1,2-DHP 8aa in ratios of 2:1 and 1:2,
respectively. In contrast, a weak Brønsted acid such as AcOH did not give any products, and only the
starting materials were recovered. These results indicate that the acidity of the catalyst significantly
affected the yield and regioselectivity of the products. On the other hand, neither aminothiourea 1a nor
DFA-1a co-catalyst furnished any of the desired DHP's in the same reaction. In an attempt to decrease
the Brønsted basicity of bifunctional thiourea, we used hydroxythioureas 1b and 1c with DFA, but this
only had marginal effects on the chemical yield and stereoselectivity. However, the desired product 7aa
was obtained in 74% yield with better regio- and enantioselectivities (7aa/8aa = 72/17 and 39% ee) with
the use of 10 mol% of DFA-chiral N-arylaminothiourea 1f as a co-catalyst.
Table 1. Initial screening of various catalysts for the synthesis of 1,4-DHP 7aa.a
R2
CO2Et
10 mol% thiourea 1
CO2Et
10 mol% Brænsted acid
R1 NH CO2Et
+
CHO
R2
N
R1
+
R2
N
R1
toluene, rt
5a (R1 = 4-MeO-C6H4)
6a (R2 = 4-NO2-C6H4)
8aa
7aa
Conversion (%) b
7aa
Yield (%) c
8aa
Yield (%) c
Entry Thiourea
BA
Time (h)
7aa
40
40
64
35
0
8aa
6
Ee (%) d
Ee (%) d
1
2
None
None
HBF4
TfOH
TFA
24
24
24
24
24
48
48
36
36
24
-
-
-
-
-
1
-
-
-
3
None
35
64
0
-
-
-
4
None
DFA
AcOH
None
DFA
DFA
DFA
DFA
-
-
-
-
5
None
-
-
-
-
6
(R, R)-1a
(R, R)-1a
(R, R)-1b
(R, R)-1c
(S, S)-1f
0
0
-
-
-
-
7
0
0
-
-
-
-
8
46
29
79
47
56
19
33
24
72
1
1
41
48
17
1
1
0
9
10
39 (R)
a
The reactions were carried out with 5a (0.1 mmol), 6a (0.1 mmol), thiourea (10 mol%) and Brøsted acid
b
1
c
(10 mol%) in toluene (1 mL) at room temperature; Conversion as determined by H-NMR; Isolated yield;
d Determined by HPLC.
Since the co-catalysts DFA and N-arylaminothiourea 1f gave good results, a wide range of Brønsted
acids were next examined in the presence of 1f (Table 2). As a result, while the addition of acids [HBF4,
TfOH, TFA, TCA, perfluorobenzoic acid (PFB)] stronger than DFA (entries 2–6) led to a decrease in
enantioselectivity, the concurrent use of 1f and a weak acid such as AcOH or BzOH significantly
improved the enantioselectivity to give the same enantiomer (R)-7aa with more than 70% ee, albeit in

Molecules 2010, 15
8310
low yield (entries 7 and 8). Since the reaction did not occur with either AcOH or bifunctional thiourea
1f, we can surmise that bifunctional thiourea 1f would activate AcOH by forming H-bond complex A or
−
ion-pair complex B. Since AcO− is well-known to be a good H-bond acceptor, in contrast to BF4 and
OTf−, the H-bond complex A could be the actual catalyst. Unfortunately, despite many trials with AcOH
and BzOH under various conditions, the chemical yield could not be enhanced without a decrease in ee.
Table 2. Effect of Brønsted acids in the presence of 1f for the synthesis of 1,4-DHP 7aa.
R2
CO2Et
10 mol% (S,S)- 1f
R1 NH CO2Et
CHO
10 mol% Brænsted acid
+
R2
N
R1
toluene, rt
5a (R1 = 4-MeO-C6H4)
6a (R2 = 4-NO2-C6H4)
(R)-7aa
Entry
Brøsted acid
HBF4
Time (h)
Yield (%) b
Ee (%) c
16
1
2
3
4
5
6
7
8
48
48
46
46
48
24
48
48
68
78
64
83
72
61
11
17
TfOH
19
TFA
29
TCA
34
DFA
39
C6F5CO2H
AcOH
BzOH
37
78
75
a The reactions were carried out with 5a (0.1 mmol), 6a (0.1 mmol), thiourea (S, S)-1f (10 mol%) and Brøsted
acid (10 mol%) in toluene (1 mL) at room temperature; b Isolated yield. c Determined by HPLC.
Therefore, we selected DFA as an optimized Brønsted acid and turned our attention to N-aryl-
aminothioureas 1d-h to improve the stereoselectivity (Table 3). Due to the instability of enamino ester
5a under the reaction conditions, the slow addition of 5a to the reaction mixture of 6a and co-catalyst
1f•DFA in toluene was examined, which resulted in the exclusive formation of 4aa in 86% yield with
50% ee (entry 1). Thus, DFA-catalyzed reactions with several bifunctional thioureas 1e-h were carried
out under slow-addition conditions. The use of phenyl- and mono-substituted anilines 1d and 1e as
catalysts led to a slight decrease in ee (entries 2 and 3). In contrast, the catalysts 1g bearing a 2,4-
dimethoxyphenyl group gave the same product with a slightly enhanced enantioselectivity, while a
similar result was obtained with more bulky catalyst 1h bearing a 2-fluoro-4-isopropoxyaniline group
(entries 4 and 5). Furthermore, other enamino esters 5b and 5c, prepared from different primary amines,
also underwent cyclization to afford the corresponding products 7ba and 7ca with moderate ee's (entries
6 and 7). Despite several trials, we could not improve the enantioselectivity of 3,4-disubstituted 1,4-
DHP's 7aa-7ca.

Molecules 2010, 15
8311
Table 3. Effect of N-arylaminothioureas in the presence of DFA for the synthesis of 1,4-DHP's.a
R2
10 mol% thiourea 1
R1 NH
CO2Et
10 mol% DFA
CO2Et
CHO
+
R2
6a (R2 = 4-NO2-C6H4)
toluene, rt,12 h
5a (R1 = 4-MeO-C6H4)
5b (R1 = 4-Cl-C6H4)
5c (R1 = C6H5CH2)
N
R1
7
Entry
Thiourea 1
(S, S)-1f
β-Enamino ester 5
Product 7
Yield (%) b
Ee (%) c
50 (R)
42 (S)
41 (S)
55 (R)
50 (R)
49 (R)
45 (R)
1
2
3
4
5
6
7
5a
5a
5a
5a
5a
5b
5c
7aa
7aa
7aa
7aa
7aa
7ba
7ca
86
86
47
91
92
78
83
(R, R)-1d
(R, R)-1e
(S, S)-1g
(S, S)-1h
(S, S)-1h
(S, S)-1h
a Reaction conditions: Slow addition (0.01 mmol/30 min) of β-enamino esters 5a-c (0.1 mmol) to a mixture of
α,β-unsaturated aldehydes 6a (0.1 mmol), thiourea 1 (10 mol%) and DFA (10 mol%) in toluene (1 mL) at
b
room temperature. The mixture was stirred for an additional 12 h after completion of the addition; Isolated
yield; c Determined by HPLC.
2.3. Application of new thiourea-ammonium salts to the synthesis of 2,3,4-trisubstituted 1,4-DHP's
Having succeeded in the catalytic asymmetric synthesis of 3,4-disubstituted 1,4-DHP's, we next
applied this method to the asymmetric synthesis of 2,3,4-trisubstituted 1,4-DHP's (Table 4). For this
purpose, we first studied the reaction of enamino ester 5d, derived from ethyl acetoacetate and 4-
methoxyaniline, and 3-(4-nitrophenyl)acrylaldehyde 6a under the optimized conditions using co-
catalysts DFA•1f-h. In fact, all of the reactions provided the desired product 7da in 65–93% yields and
the highest ee was achieved with DFA•1h complex (entries 1-3). Further experiments with β-enamino
esters 5e-j and α,β-unsaturated aldehydes 6a-f were performed with DFA•1h (entries 4-14). With regard
to the enamino esters, tert-butyl ester 5e and β-phenyl-substituted analogue 5f could be used as
nucleophiles without a significant decrease in ee (entries 4 and 5). In addition, both electron-rich aryl
and arylmethyl groups of 5g-j could also be tolerated as the substituent (R1) on the nitrogen (entries 6
and 12-14). Moreover, the reactions of several unsaturated aldehydes 6b-f bearing different aryl groups
with 5g provided the corresponding 1,4-DHP's in reasonable yields, but electron-deficient substrates 6d-
f generally led to better enantioselectivity than electron-rich substrates 6b and 6c (entries 7–11). The
reaction of β-enamino esters with a benzyl group at the nitrogen (R1) and a methyl group at the β-
position (R3) afforded the corresponding 1,4-DHP's 7ia and 7ja with good enantioselectivities (entries
13 and 14).

Molecules 2010, 15
Table 4. Scope of the substrates 5 and 6 for the synthesis of 2,3,4,-trisubstituted 1,4-DHP's.a
8312
R2
10 mol% 1
10 mol% DFA
O
COR4
R3
R1 NH
R3
R4
CHO
R2
+
toluene, rt, 12 h
N
R1
5d-j
6a-f
7
Yield
Ee
Entry
Thiourea
5
R1
R3
R4
6
R2
7
(%)
84
65
93
81
85
96
61
56
62
55
70
78
81
65
(%)
61
56
66
51
61
66
44
38
53
58
44
38
80
77
1
2
(S, S)-1f
(S, S)-1g
(S, S)-1h
(S, S)-1h
(S, S)-1h
(S, S)-1h
(S, S)-1h
(S, S)-1h
(S, S)-1h
(S, S)-1h
(S, S)-1h
(S, S)-1h
(S, S)-1h
(S, S)-1h
5d
5d
5d
5e
5f
4-MeO-C6H4
4-MeO-C6H4
4-MeO-C6H4
4-MeO-C6H4
4-MeO-C6H4
Me
Me
Me
OEt
OEt
OEt
6a
6a
6a
6a
6a
6a
6b
6c
6d
6e
6f
4-NO2-C6H4
4-NO2-C6H4
4-NO2-C6H4
4-NO2-C6H4
4-NO2-C6H4
4-NO2-C6H4
C6H5
7da
7da
7da
7ea
7fa
7ga
7gb
7gc
7gd
7ge
7gf
7ha
7ia
3
4
Me Ot-Bu
5
Ph
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
6
5g
5g
5g
5g
5g
5g
5h
5i
3,4-MeO-C6H3
3,4-MeO-C6H3
3,4-MeO-C6H3
3,4-MeO-C6H3
3,4-MeO-C6H3
3,4-MeO-C6H3
4-Cl-C6H4
Me
Me
Me
Me
Me
Me
Me
Me
Me
7
8
4-MeO-C6H4
4-F-C6H4
9
10
11
12
13
3-F-C6H4
2-F-C6H4
6a
6a
6a
4-NO2-C6H4
4-NO2-C6H4
4-NO2-C6H4
C6H4CH2
14
5j
4-MeO C6H3CH2
7ja
a
Reaction conditions: Slow addition (0.01 mmol/30 min) of β-enaminoesters 5d-j (0.1 mmol) to a mixture of
α,β-unsaturated aldehydes 6a-f (0.1 mmol), thiourea 1 (10 mol%) and DFA (10 mol%) in toluene (1 mL) at
b
room temperature. The mixture was stirred for an additional 12 h after completion of the addition. Isolated
yield. c Determined by HPLC.
2.4. Utility of thiourea-ammonium salts derived from strong Brønsted acids and anilinothioureas
We have demonstrated that H-bonding complexes A, prepared from anilinothiourea and DFA,
efficiently catalyzed the three-component coupling via route b to give the functionalized 1,4-DHP's with
moderate to good enantioselectivity. We next examined the alternative reaction path via route a with the
Brønsted acid-anilinothiourea co-catalysts. The reaction was performed as follow. β-Keto ester 10 was
added to the preformed imines, prepared from α,β-unsaturated aldehyde 6a and p-anisidine 9, in the
presence of various co-catalysts composed of bifunctional thioureas 1d-h and Brønsted acids such as
DFA, TFA, TfOH, and HBF4 (Table 5). Initially we examined the best co-catalyst DFA•(S,S)-1h for
route b, which gave the same product (R)-7da in 64% yield with a slightly low ee (entry 1). Although the
same treatment of imine and 10 with co-catalyst TFA•(S,S)-1h led to a similar result, an enantiomer of
the product (S)-7da was obtained, albeit with poor enantioselectivity, with the use of strong Brønsted
acids (TfOH, and HBF4) as co-catalysts (entries 2–4). The same trend was observed with other
bifunctional thioureas (S,S)-1f, g and (R,R)-1d, e (entries 5–14). Among the various co-catalysts prepared
from 1d-h, HBF4•(R,R)-1e gave (R)-7da with the highest ee (69% ee) (entry 14). Consequently, we have
established a method for the synthesis of both enantiomers of highly functionalized 1,4-DHP's by simply
switching the Brønsted acids (DFA and HBF4) used as the co-catalysts, starting from the same substrates.

Molecules 2010, 15
Table 5. Three-component cyclization catalyzed by Brønsted acid-anilinothiourea co-catalysts.a
8313
Entry
Thiourea
(S, S)-1h
(S, S)-1h
(S, S)-1h
(S, S)-1h
(S, S)-1f
(S, S)-1f
(S, S)-1f
(S, S)-1f
(S, S)-1g
(S, S)-1g
(S, S)-1g
(R, R)-1d
(R, R)-1e
(R, R)-1e
Brønsted acid
DFA
Time
48
24
60
72
48
24
48
72
48
24
60
96
96
72
Yield (%) b
Ee (%) c
50 (R)
49 (R)
20 (S)
28 (S)
43 (R)
25 (R)
50 (S)
37 (S)
39 (R)
1 (R)
1
2
64
73
82
69
53
76
82
61
49
82
77
56
69
52
TFA
3
TfOH
HBF4
DFA
4
5
6
TFA
7
TfOH
HBF4
DFA
8
9
10
11
12
13
TFA
TfOH
TfOH
TfOH
HBF4
33 (S)
39 (R)
61 (R)
69 (R)
14
a
Reaction conditions: The mixture of 6a (0.15 mmol), p-anisidine 9 (0.1 mmol), thiourea 1 (10 mol%) and
Brønsted acid (10 mol%) in toluene (1 mL) was stirred at room temperature for 30 min. After keto ester 10
(0.2 mmol) was the added, the resulting mixture was stirred at rt; b Isolated yield. c Determined by HPLC.
2.5. Proposed reaction mechanism of Brønsted acid-anilinothiourea co-catalysis
In a former reaction with carboxylic acid-thiourea co-catalysts, H-bonded ammonium complex A
would be equilibrated with free acid (HX) and uncomplexed thiourea 1 due to the weak acidity of HX
(Figure 1). If the free acid can promote the reaction, both the catalyzed and uncatalyzed reactions would
proceed, to give the product in low enantioselectivity. This is why DFA, which has medium acidity,
gave better results than strong acids such as TFA and TCA. In contrast, high enantioselectivity was
achieved with the AcOH•(S,S)-1f co-catalyst, since free AcOH has no catalytic activity for the
cyclization. This result obviously indicates that an appropriate bifunctional thiourea can activate weak
acids to catalyze three-component cyclization, even though the co-catalysts must be weaker acids than
the free acids. To explain this result, we speculate that the conjugate base (X-) should play an important
role for acceleration of the reaction. Based on this assumption, a proposed reaction mechanism is shown
in Figure 3. Initially, the ammonium carboxylate complex A, in which each of two ammonium protons
interacts with the carboxylate anion or ortho-substituent of the aniline via H-bond, would be formed
from the catalyst 1 and HX. The aldehyde would then interact with one of the ammonium protons of the
co-catalyst from the less-hindered side. The protonated aldehyde would be attacked from the bottom
face (Si-face) by the enamino ester, which is concurrently deprotonated by the conjugate base. In this
transition-state TS-(a), which is energetically more stable than TS-(b), both nucleophile 5 and
electrophile 6 are activated simultaneously by HX complexed with the bifunctional anilinothiourea, to
generate the desired (S)-product, when (R,R)-thiourea is used.

Molecules 2010, 15
8314
Similarly, the reaction of α,β-unsaturated imine and β-keto ester with DFA-(R,R)-thiourea 1 can be
explained by TS-(c) in Figure 3. In this case, (Z)-imine [28] should coordinate to the ammonium proton
of the same co-catalyst and the nucleophile approaches from the same Si-face to predominantly give the
(S)-isomer. On the other hand, the ion-pair complex B would be exclusively generated when strong
acids such as TfOH, and HBF4 are reacted with bifunctional thiourea 1. As shown in Figure 3, in TS-(d),
the (Z)-imine coordinates to the ammonium proton of the ion-pair complex B in the same way as in TS-
(c), but the nucleophile is considered to approach from the less-hindered upper side (Re-face) without
any assistance of the conjugate base, since the ammonium proton of the ion-pair complex B should be
more acidic than that of the H-bonding complex A, to predominantly give the (R)-isomer.
Figure 3. Proposed TS models for the co-catalyzed three-component reaction.
S
S
H
H
Ar
N
H
Ar
N
H
N
H
N
H
F
F
N
N
O
H
O
H
O
O
O
R
O
R
R1
R3
R1
R3
H
H
OR
OR
N
O
N
O
EtO
EtO
(b) unfavorable comformation in route b
(a) favorable comformation in route b
S
S
H
H
BF4
Ar
N
H
N
H
Ar
N
H
N
H
OMe
F
N
H
N
O
H
N
N
R3
O
R
O
H
O
OR
O
H
O
R3
EtO
EtO
(c) favorable comformation of the reaction
catalyzed by thiourea-DFA
(d) favorable comformation of the reaction
catalyzed by thiourea-HBF4
3. Experimental
3.1. General
All non-aqueous reactions were carried out under a positive atmosphere of argon in dried glassware
unless otherwise noted. Solvents were dried and distilled according to standard protocols. Materials
were obtained from commercial suppliers and used without further purification except when otherwise
noted. All melting points were determined on a Yamamoto micro melting point apparatus and are
1
uncorrected. H- and 13C-NMR spectra were recorded in CDCl3 at 500 or 400 MHz, and at 125 or
100 MHz, respectively; Tetramethylsilane (TMS) was used as an internal standard. IR spectra were
recorded on a JASCO FT/IR-410 Fourier-tranfer infrared spectrometer. Low and High resolution mass
spectra were obtained by EI or FAB method. Optical rotations were recorded on a JASCO DIP-360

Molecules 2010, 15
8315
polarimeter with a path length of 1 cm; concentrations are quoted in mg (2 mL). [α]D values are
measured in 10−1 deg cm2 g−1. Enantiometeric excess was determined by high performance liquid
chromatography (HPLC) analysis.
3.2. Synthesis of 1-(3,5-bis(trifluoromethyl)phenyl)-3-((1R,2R)-2-(2-methoxyphenylamino)cyclohexyl)
thiourea [(R, R)-1e]
To a solution of (1R,2R)-1,2-diaminocyclohexane (251 mg, 2.20 mmol) in toluene (10 mL) was
added 2-bromoanisole (374 mg, 2.00 mmol), rac-BINAP (124 mg, 0.20 mmol), sodium t-butoxide (577
mg, 6.00 mmol) and Pd(OAc)2 (22.5 mg, 0.10 mmol). After the mixture was stirred at 80 °C for 12 h
and cooled at ambient temperature, the mixture was filtered through a Celite pad. The filtrate was
concentrated in vacuo, The resulting residue was passed through silica gel pad (hexane-ethyl acetate =
1:1 to CHCl3-CH3OH- aq.NH3 = 100:10:1) to give crude (1R,2R)-N1-(2-methoxyphenyl)cyclohexane-
1,2-diamine, which was used in next reactions without further purification. This crude material was
dissolved with CH2Cl2 (5 mL), and added 1-isothiocyanato-3,5-bis(trifluoromethyl)benzene (81.5 mg,
0.30 mmol). After the mixture was stirred at ambient temperature for 1 h, the reaction mixture was
concentrated in vacuo. The residue was purified by silica gel chromatography (hexane:ethyl acetate =
5:1) to give thiourea (R, R)-1e (95.1 mg, 0.193 mmol, 10%) as a colorless amorphous solid; IR (ATR)
3326, 2925, 1507, 1091 cm-1;1H-NMR (500 MHz, DMSO-d6 at 100 °C) δ (ppm) 9.68 (s, 1H), 8.17 (s,
2H), 7.94 (br, 1H), 7.61 (s, 1H), 6.76 (d, J = 8.0 Hz, 1H), 6.75 (dd, J = 8.0 and 8.0 Hz, 1H), 6.65 (d,
J = 8.1 Hz, 1H), 6.51 (dd, J = 8.1 and 8.0 Hz, 1H), 4.72 (br, 1H), 4.41-4.38 (m, 1H), 3.71 (s, 3H), 3.33-
3.30 (m, 1H), 2.16-2.06 (m, 2H), 1.78-1.64 (m, 2H), 1.49-1.18 (m, 4H); 13C-NMR (125 MHz, DMSO-d6
2
1
at 100 °C) δ (ppm) 180.4, 146.4, 141.7, 137.3, 129.8 (q, J(C, F) = 33.8 Hz), 122.8 (q, J(C, F) = 271 Hz),
121.8, 120.7, 115.4, 115.1, 110.4, 109.5, 56.3, 55.9, 55.2, 31.6, 30.7, 23.8, 23.4; MS (FAB+) m/z: 492
(M + H+, 100); HRMS (FAB+) m/z: calcd for C22H24F6N3OS (M + H+): 492.1544. Found: 492.1537;
[α]D25 = -6.1 (c 1.07, CHCl3).
3.3. Synthesis of 1-(3,5-bis(trifluoromethyl)phenyl)-3-((1R,2R)-2-(phenylamino)cyclohexyl)thiourea [(R,
R)-1d]
A procedure similar to that described for the preparation of 1e afforded 1d (15%). Colorless
1
amorphous solid; IR (ATR) 3327, 2932, 2858, 1536, 1091 cm−1; H-NMR (500 MHz, DMSO-d6) δ
(ppm) 9.95 (s, 1H), 8.19 (br, 1H), 8.18 (s, 2H), 7.69 (s, 1H), 7.04 (dd, J = 8.1 and 7.5 Hz, 2H), 6.63 (d,
J = 8.1 Hz, 2H), 6.50 (t, J = 7.5 Hz, 1H), 5.36 (d, J = 8.6 Hz, 1H), 4.27-4.21 (m, 1H), 3.42-3.29 (m, 1H),
2.33-2.01 (m, 2H), 1.78-1.63 (m, 2H), 1.41-1.13 (m, 4H); 13C-NMR (125 MHz, DMSO-d6) δ (ppm)
179.9, 148.1, 141.8, 130.1 (q, 2J(C, F) = 33.4 Hz), 128.8, 122.1 (q, 1J(C, F) = 272 Hz), 121.8, 115.9, 115.6,
112.5, 56.5, 55.1, 31.5, 30.7, 24.1, 23.8; MS (FAB+) m/z: 462 (M + H+, 100); HRMS (FAB+) m/z: calcd
for C21H22F6N3S (M + H+): 462.1439. Found: 462.1429; [α]D23 = 34.9 (c 1.02, CHCl3).
3.4. Synthesis of (1S,2S,1’S)-3f and (1R,2R,1’S)-4f
To a solution of aziridine 2 (603 mg, 3.00 mmol) in CH3CN (15 mL) was added 2-fluoro-4-
methoxyaniline (430 mg, 3.05 mmol) and tris(perfluorophenyl)borane (154 mg, 0.300 mmol). After the

Molecules 2010, 15
8316
mixture was stirred at 65 °C for 36 h and cooled at ambient temperature, the reaction mixture was added
0.3 g of Amberlyst A-21 resin and 5 mL of dichloromethane. The mixture was stirred for 1 h then the
resin was removed by filtration through a cotton plug. The solvent was removed in vacuo and the
residue was purified by flash amino silica gel chromatography (hexane-ethyl acetate = 5:1) to give
(1S,2S,1’S)-3f (440 mg, 1.28 mmol, 43%) as a clear oil and (1R,2R,1’S)-4f (175 mg, 0.51 mmol, 17%)
as a clear oil that solidified to a white solid after standing.
(1S,2S)-N1-(2-Fluoro-4-methoxyphenyl)-N2-((S)-1-phenylethyl)cyclohexane-1,2-diamine [(1S,2S,1’S)-
3f]: Colorless oil; IR (ATR) 3330, 2979, 2921 cm−1; 1H-NMR (500 MHz, CDCl3) δ (ppm) 7.34-7.19 (m,
5H), 6.75 (dd, J = 9.5 and 9.5 Hz, 1H), 6.65 (dd, J = 12.5 and 2.5 Hz, 1H), 6.57 (dd, J = 9.5 and 2.5 Hz,
1H), 3.89 (q, J = 7.5 Hz, 1H), 3.74 (s, 3H), 3.67 (br, 1H), 2.93 (dt, J = 3.5 and 9.5 Hz, 1H), 2.48 (dt,
J = 3.5 and 9.9 Hz, 1H), 2.14-2.09 (m, 1H), 1.89-1.83 (m, 1H), 1.68-1.57 (m, 2H), 1.32 (d, J = 7.5 Hz,
3H), 1.29-1.00 (m, 4H); 13C-NMR (125 MHz, CDCl3) δ (ppm) 152.8 (d, 1J(C, F) = 242 Hz), 151.9 (d, 3J(C,
F) = 6.0 Hz), 147.3, 130.5 (d, 2J(C, F) = 12.0 Hz), 128.3, 126.6, 126.5, 115.2 (d, 3J(C, F) = 3.6 Hz), 109.4 (d,
4J(C, F) = 3.5 Hz), 102.3 (d, 2J(C, F) = 22.8 Hz), 60.5, 59.0, 56.2, 55.9, 32.72, 32.66, 24.79, 24.76, 24.1; MS
+
+
(FAB+) m/z: 342 (M , 100); HRMS (FAB+) m/z: calcd for C21H27FN2O (M ): 342.2107. Found:
342.2110; [α]D26 = 34.5 (c 1.16, CHCl3).
(1R,2R)-N1-(2-Fluoro-4-methoxyphenyl)-N2-((S)-1-phenylethyl)cyclohexane-1,2-diamine [(1R,2R,1’S)-
4f]: white solid; Mp. 57–58 °C (hexane); IR (ATR) 3359, 2973, 2924 cm−1; 1H NMR (500 MHz, CDCl3)
δ (ppm) 7.38-7.24 (m, 5H), 6.71 (dd, J = 9.2 and 9.2 Hz, 1H), 6.64 (dd, J = 13.1 and 2.9 Hz, 1H), 6.58
(dd, J = 9.2 and 2.9 Hz, 1H), 3.90 (q, J = 7.5 Hz, 1H), 3.74 (s, 3H), 3.25 (br, 1H), 2.98-2.96 (m, 1H),
2.18-2.14 (m, 1H), 2.08-2.02 (m, 2H), 1.70-1.59 (m, 2H), 1.33 (d, J = 7.5 Hz, 3H), 1.29-1.05 (m, 3H),
1
0.94-0.85 (m, 1H); 13C NMR (125 MHz, CDCl3) δ (ppm) 152.7 (d, J(C, F) = 238 Hz), 151.8 (d,
2
3
3J(C, F) = 9.5 Hz), 145.8, 130.2 (d, J(C, F) = 11.9 Hz), 128.6, 126.8, 126.4, 114.8 (d, J(C, F) = 3.6 Hz),
4
2
109.4 (d, J(C, F) = 3.6 Hz), 102.4 (d, J(C, F) = 22.7 Hz), 58.4, 57.9, 55.9, 54.3, 32.3, 31.3, 25.3, 24.9,
24.4; MS (FAB+) m/z: 342 (M +, 100); HRMS (FAB+) m/z: calcd for C21H27FN2O (M +): 342.2107.
26
Found: 342.2109; [α]D = 50.7 (c 1.03, CHCl3). Single crystals suitable for X-ray diffraction were
grown by cooling a solution of (1R, 2R, 1’S)-4f in hexane in a closed tube to -20 ºC. The crystal data of
(1R, 2R, 1’S)-4f are as follows: space group, P21; a = 8.5306(19) Å, b = 14.839(4) Å, c = 14.805(4) Å,
V = 1874.1(8) Å3, Z = 4, Dcalc = 1.214 g/cm3, R = 0.0568, Rw = 0.1334, GOF = 0.930. CCDC 768496
contains the supplementary crystallographic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
3.5. Synthesis of 1-(3,5-bis(trifluoromethyl)phenyl)-3-((1S,2S)-2-(2-fluoro-4-methoxyphenylamino)
cyclohexyl)thiourea [(S, S)-1f]
To a solution of (1S,2S,1’S)-3f (350 mg, 1.02 mmol) in CH3OH (15 mL) was added 10% Pd/C
(100 mg) and ammonium formate (1.50 g). After the mixture was stirred at 60 °C for 12 h and cooled at
ambient temperature, the mixture was filtered through through a pad of celite. The filtrate was
concentrated in vacuo, The resulting material was dissolved with CH2Cl2 (5 mL), and added 1-
isothiocyanato-3,5-bis(trifluoromethyl)benzene (280 mg, 1.00 mmol). After the mixture was stirred at
ambient temperature for 3 h, the reaction mixture was concentrated in vacuo. The residue was purified

Molecules 2010, 15
8317
by silica gel chromatography (hexane-ethyl acetate = 5:1) to give (S, S)-1f (436 mg, 0.856 mmol, 84%)
1
as a colorless amorphous solid; IR (ATR) 3275, 2937, 1514, 1278, 1090 cm−1; H-NMR (500 MHz,
DMSO-d6) δ (ppm) 9.98 (s, 1H), 8.27 (br, 1H), 8.17 (s, 2H), 7.69 (s, 1H), 6.78 (dd, J = 9.2 and 8.6 Hz,
1H), 6.72 (dd, J = 13.2 and 2.3 Hz, 1H), 6.61 (dd, J = 8.6 and 2.3 Hz, 1H), 4.69-4.66 (m, 1H), 4.39 (br,
13
1H), 3.65 (s, 3H), 3.32-3.26 (m, 1H), 2.21-2.02 (m, 2H), 1.74-1.67 (m, 2H), 1.41-1.20 (m, 4H); C-
3
1
NMR (125 MHz, DMSO-d6) δ (ppm) 180.2, 150.4 (d, J(C, F) = 9.5 Hz), 151.3 (d, J(C, F) = 237 Hz),
141.9, 130.2 (q, 2J(C, F) = 32.2 Hz), 129.8 (d, 2J(C, F) = 11.9 Hz), 123.2 (q, 1J(C, F) = 272 Hz), 121.8, 115.8,
2
113.5, 109.6, 102.1 (d, J(C, F) = 22.6 Hz), 79.2, 56.7, 55.5, 31.9, 31.1, 24.4, 24.0; MS (FAB+) m/z: 438
(M + H+, 100); HRMS (FAB+) m/z: calcd for C22H23F7N3OS (M + H+): 510.1450. Found: 510.1438;
[α]D24 = -49.0 (c 1.02, CHCl3).
3.6. Synthesis of (1S,2S,1’S)-3g and (1R,2R,1’S)-4g
By a similar procedure described for the preparation of (1S,2S,1’S)-3f and (1R,2R,1’S)-4f, (1S,2S,
1’S)-3g (550 mg, 1.55 mmol, 52%) and (1R,2R,1’S)-4g (270 mg, 0.76 mmol, 25%) were obtained from
2 (603 mg, 3.00 mmol) and 2,4-dimethoxyaniline (470 mg, 3.07 mmol).
(1S,2S)-N1-(2,4-Dimethoxyphenyl)-N2-((S)-1-phenylethyl)cyclohexane-1,2-diamine
[(1S,2S,1’S)-3g]:
Colorless oil; IR (ATR) 3330, 2978, 2922 cm−1; H-NMR (500 MHz, CDCl3) δ (ppm) 7.34-7.18 (m,
5H), 6.64 (d, J = 8.6 Hz, 1H), 6.47 (d, J = 2.3 Hz, 1H), 6.40 (dd, J = 8.6 and 2.3 Hz, 1H), 3.89 (q,
J = 6.9 Hz, 1H), 3.85 (s, 3H), 3.76 (s, 3H), 2.96 (dt, J = 3.6 and 9.9 Hz, 1H), 2.49 (dt, J = 3.8 and 9.7
Hz, 1H), 2.15-2.11 (m, 1H), 1.84-1.80 (m, 1H), 1.66-1.60 (m, 2H), 1.31 (d, J = 6.9 Hz, 3H), 1.28-1.00
(m, 4H); 13C-NMR (125 MHz, CDCl3) δ (ppm) 152.0, 148.7, 147.5, 132.5, 128.24, 128.23, 126.6, 112.1,
104.0, 99.3, 60.7, 58.7, 56.4, 55.8, 55.5, 32.8, 32.6, 24.9, 24.8, 24.2; MS (FAB+) m/z: 354 (M+, 100);
1
26
HRMS (FAB+) m/z: calcd for C22H30N2O2 (M +): 354.2307. Found: 354.2292; [α]D = 41.0 (c 0.98,
CHCl3).
(1R,2R)-N1-(2,4-Dimethoxyphenyl)-N2-((S)-1-phenylethyl)cyclohexane-1,2-diamine [(1R,2R,1’S)-4g)]:
1
Colorless oil; IR (ATR) 3335, 2974, 2926 cm−1; H-NMR (500 MHz, CDCl3) δ (ppm) 7.37-7.24 (m,
5H), 6.61 (d, J = 8.6 Hz, 1H), 6.46 (d, J = 2.9 Hz, 1H), 6.40 (dd, J = 8.6 and 2.9 Hz, 1H), 3.91 (q,
J = 6.9 Hz, 1H), 3.85 (s, 3H), 3.76 (s, 3H), 3.05-2.98 (m, 1H)., 2.18-2.04 (m, 3H), 1.69-1.58 (m, 2H),
13
1.33 (d, J = 6.9 Hz, 3H), 1.24-1.05 (m, 3H), 0.91-0.82 (m, 1H); C-NMR (125 MHz, CDCl3) δ (ppm)
151.9, 148.60, 148.59, 132.1, 128.5, 126.7, 126.5, 111.8, 104.1, 99.3, 60.4, 58.1, 57.9, 55.8, 55.8, 32.2,
31.3, 25.4, 25.0, 24.5; MS (FAB+) m/z: 354 (M+, 100); HRMS (FAB+) m/z: calcd for C22H30N2O2 (M+):
354.2307. Found: 354.2291; [α]D26 = 20.8 (c 1.18, CHCl3).
3.7. Synthesis of 1-(3,5-bis(trifluoromethyl)phenyl)-3-((1S,2S)-2-(2,4-dimethoxyphenylamino)cyclo-
hexyl)thiourea [(S, S)-1g]
By a similar procedure described for the preparation of (S,S)-1f, (S,S)-1g (502 mg, 0.96 mmol, 72%)
was obtained from (1S,2S,1’S)-3g (470 mg, 1.33 mmol); Colorless amorphous Solid; IR (ATR) 3331,
2935, 1510, 1277, 1091 cm−1; 1H-NMR (500 MHz, DMSO-d6) δ (ppm) 9.94 (s, 1H), 8.25 (br, 1H), 8.18
(s, 2H), 7.70 (s, 1H), 6.55 (d, J = 8.6 Hz, 1H), 6.47 (d, J = 2.9 Hz, 1H), 6.37 (dd, J = 8.6 and 2.9 Hz,

Molecules 2010, 15
8318
1H), 4.47-4.31 (m, 2H), 3.71 (s, 3H), 3.65 (s, 3H), 3.31-3.14 (m, 1H), 2.20-2.01 (m, 2H), 1.77-1.61 (m,
2H), 1.46-1.06 (m, 4H); 13C-NMR (125 MHz, DMSO-d6) δ (ppm) 180.2, 150.9, 147.4, 141.9, 130.1 (q,
1
2J(C, F) = 31.0 Hz), 123.2 (q, J(C, F) = 272 Hz), 121.8, 115.8, 109.9, 104.3, 99.2, 56.6, 56.5, 55.4, 55.3,
31.9, 31.1, 31.2, 24.4, 24.0; MS (FAB+) m/z: 438 (M + H+, 100); HRMS (FAB+) m/z: calcd for
C23H26F6N3O2S (M + H+): 522.1650. Found: 522.1633; [α]D25 = -14.5 (c 1.25, CHCl3).
3.8. Synthesis of (1S,2S,1’S)-3h and (1R,2R,1’S)-4h
By a similar procedure described for the preparation of (1S,2S,1’S)-3f and (1R,2R,1’S)-4f, (1S,2S,
1’S)-3h (425 mg, 1.14 mmol, 57%) and (1R,2R,1’S)-4h (85 mg, 0.22 mmol, 11%) were obtained from 2
(403 mg, 2.00 mmol) and 2-fluoro-4-isopropoxyaniline (340 mg, 2.00 mmol).
(1S,2S)-N1-(2-Fluoro-4-isopropoxyphenyl)-N2-((S)-1-phenylethyl)cyclohexane-1,2-diamine [(1S, 2S,
1
1’S)-3h]: Colorless oil; IR (ATR) 3335, 2974, 2926 cm−1; H-NMR (500 MHz, CDCl3) δ (ppm) 7.34-
7.19 (m, 5H), 6.74 (dd, J = 9.1 and 8.6 Hz, 1H), 6.65 (dd, J = 13.2 and 2.9 Hz, 1H), 6.57 (dd, J = 8.6 and
2.9 Hz, 1H), 4.35 (seq, J = 6.3 Hz, 1H), 3.89 (q, J = 6.9 Hz, 1H), 3.69 (br, 1H), 2.93 (dt, J = 3.5 and 9.9
Hz, 1H), 2.47 (dt, J = 4.0 and 9.8 Hz, 1H), 2.14-2.10 (m, 1H), 1.87-1.83 (m, 1H), 1.67-1.61 (m, 2H),
13
1.31 (d, J = 6.9 Hz, 3H), 1.29 (d, J = 6.3 Hz, 6H), 1.28-1.00 (m, 4H); C-NMR (125 MHz, CDCl3) δ
1
(ppm) 152.7 (d, J(C, F) = 237 Hz), 149.8 (d, 3J(C, F) = 9.5 Hz), 147.2, 130.5 (d, 2J(C, F) = 12.1 Hz), 128.3,
3
4
2
126.6, 126.5, 114.9 (d, J(C, F) = 4.8 Hz), 112.3 (d, J(C, F) = 3.6 Hz), 104.7 (d, J(C, F) = 20.7 Hz), 71.2,
60.5, 58.9, 56.2, 32.71, 32.66, 24.77, 24.74, 24.1, 22.1; MS (FAB+) m/z: 370 (M+, 100); HRMS (FAB+)
m/z: calcd for C23H31FN2O (M +): 370.2420. Found: 370.2414; [α]D26 = 30.0 (c 1.22, CHCl3).
(1R,2R)-N1-(2-Fluoro-4-isopropoxyphenyl)-N2-((S)-1-phenylethyl)cyclohexane-1,2-diamine
[(1R,2R,
1’S)-4h]: Colorless oil; IR (ATR) 3361, 2977, 2923 cm−1; H-NMR (500 MHz, CDCl3) δ (ppm) 7.38-
7.24 (m, 5H), 6.69 (dd, J = 9.8 and 8.6 Hz, 1H), 6.63 (dd, J = 12.6 and 2.9 Hz, 1H), 6.57 (dd, J = 9.8 and
2.9 Hz, 1H), 4.36 (seq, J = 6.3 Hz, 1H), 3.90 (q, J = 6.9 Hz, 1H), 3.29 (br, 1H), 2.99-2.95 (m, 1H)., 2.18-
2.02 (m, 3H), 1.69-1.60 (m, 2H), 1.33 (d, J = 6.9 Hz, 3H), 1.29 (d, J = 6.3 Hz, 6H), 1.28-1.08 (m, 3H),
1
1
0.92-0.87 (m, 1H); 13C NMR (125 MHz, CDCl3) δ (ppm) 153.0 (d, J(C, F) = 237 Hz), 149.7 (d,
2
3
3J(C, F) = 9.5 Hz), 145.8, 130.4 (d, J(C, F) = 11.9 Hz), 128.6, 126.9, 126.4, 114.7 (d, J(C, F) = 4.8 Hz),
4
2
112.4 (d, J(C, F) = 2.4 Hz), 104.8 (d, J(C, F) = 22.7 Hz), 71.3, 58.4, 58.0, 54.3, 32.3, 31.3, 25.3, 24.9,
24.5, 22.1; HRMS (FAB+) m/z: calcd for C23H31FN2O (M +): 370.2420. Found: 370.2411; [α]D = 43.7
25
(c 1.18, CHCl3).
3.9. Synthesis of 1-(3,5-bis(trifluoromethyl)phenyl)-3-((1S,2S)-2-(2-fluoro-4-isopropoxyphenylamino)
cyclohexyl)thiourea [(S, S)-1h]
By a similar procedure described for the preparation of (S,S)-1f, (S,S)-1h (410 mg, 0.762 mmol,
81%) was obtained from (1S,2S,1’S)-3h (350 mg, 0.944 mmol); Colorless amorphous Solid; IR (ATR)
1
3276, 2923, 1512, 1090 cm−1; H-NMR (500 MHz, DMSO-d6 at 100 °C) δ (ppm) 9.67 (s, 1H), 8.15 (s,
2H), 7.94 (br, 1H), 7.61 (s, 1H), 6.74 (dd, J = 9.2 and 9.2 Hz, 1H), 6.61 (d, J = 13.8 Hz, 1H), 6.55 (d,
J = 9.2 Hz, 1H), 4.42-4.35 (m, 1H), 4.32 (seq, J = 5.8 Hz, 1H), 4.30 (br, 1H), 3.31-3.24 (m, 1H), 2.11-
13
2.06 (m, 2H), 1.73-1.68 (m, 2H), 1.45-1.20 (m, 4H), 1.18 (d, J = 5.8 Hz, 6H); C-NMR (125 MHz,

Molecules 2010, 15
DMSO-d6 at 100 °C) δ (ppm) 180.3, 150.9 (d, 1J(C, F) = 237 Hz), 148.4 (d, 3J(C, F) = 9.5 Hz), 141.6, 129.8
8319
2
2
1
(q, J(C, F) = 33.4 Hz), 129.6 (d, J(C, F) = 11.9 Hz), 122.7 (q, J(C, F) = 271 Hz), 121.8, 115.4, 113.6 (d,
3J(C, F) = 3.6 Hz), 112.2 (d, J(C, F) = 3.6 Hz), 104.3 (d, J(C, F) = 21.5 Hz), 70.4, 56.7, 56.6, 31.7, 30.7,
23.8, 23.5, 21.3; MS (FAB+) m/z: 438 (M + H+, 100); HRMS (FAB+) m/z: calcd for C24H27F7N3OS (M +
H+): 538.1763. Found: 538.1760; [α]D25 = -48.3 (c 1.15, CHCl3).
4
2
3.10. Preparation of (Z)-ethyl 3-(4-methoxyphenylamino)acrylate (5a)
To a solution of ethyl 3-oxopropanoate (1.16 g, 10.0 mmol) in CH2Cl2 (20 mL) was added p-anisidine
(1.23 g, 10.0 mmol) at ambient temperature. After the mixture was stirred at the same temperature
overnight, the reaction mixture was concentrated. The resulting residue was passed through silica gel
pad (hexane-ethyl acetate = 4:1) to afford the desired material as a E/Z mixture, which was recrystallized
from hexane-ethyl acetate to give the title material 5a (352 mg, 1.59 mmol, 16%, predominantly Z form)
as a pale yellow solid; Mp. 48–49 °C (ethyl acetate-hexane); IR (ATR) 3276, 2981, 2918, 1699 cm−1;
1H-NMR (500 MHz, CDCl3) δ (ppm) 9.81 (brd, J = 12.6 Hz, 1H), 7.15 (dd, J = 12.6, 8.0 Hz, 1H), 6.91
(d, J = 8.6 Hz, 2H), 6.85 (d, J = 8.6 Hz, 2H), 4.77 (d, J = 8.0 Hz, 1H), 4.17 (q, J = 7.4 Hz, 2H), 3.78 (s,
3H), 1.30 (t, J = 7.4 Hz, 3H); 13C-NMR (125 MHz, CDCl3) δ (ppm) 170.5, 155.5, 144.1, 134.5, 117.0,
114.9, 86.1, 59.1, 55.6, 14.5; MS (FAB+) m/z: 221 (M+, 100); HRMS (FAB+) m/z: calcd for C12H15NO3
(M +): 221.1052. Found: 221.1069.
3.11. Preparation of enamino esters 5b-k
Enaminoesters 5b-k were prepared using literature procedures [29]. Enaminoesters 5b-k was used in
the reactions without further purification.
3.12. General Procedure for the reaction of enaminoester 5a with 4-nitrocinnamaldehyde (6a) catalyzed
by thiourea 1 – Brønsted acid (Tables 1 and 2).
To a solution of thiourea 1 (0.010 mmol) and Brønsted acid (0.010 mmol) in toluene (1.0 mL) were
added 5a (0.10 mmol) and 6a (0.10 mmol) at ambient temperature. After being stirred at the same
temperature, the reaction mixture was concentrated in vacuo. The resulting residue was purified by silica
gel chromatography (hexane-ethyl acetate = 5:1) to give 7aa and 8aa.
Ethyl 1-(4-methoxyphenyl)-6-(4-nitrophenyl)-1,6-dihydropyridine-3-carboxylate (8aa): An orange oil;
IR (ATR) 2979, 2919, 1685, 1513 cm−1; 1H-NMR (400 MHz, CDCl3) δ (ppm) 8.20 (d, J = 8.7 Hz, 2H),
7.80 (s, 1H), 7.49 (d, J = 8.7 Hz, 2H), 6.96 (d, J = 8.8 Hz, 2H), 6.82 (d, J = 8.8 Hz, 2H), 6.58 (d,
J = 9.8 Hz, 1H), 5.66 (d, J = 5.4 Hz, 1H), 5.37 (dd, J = 9.8 and 5.4 Hz, 1H), 4.22 (q, J = 7.1 Hz, 2H),
3.77 (s, 3H), 1.30 (t, J = 7.1 Hz, 3H); 13C-NMR (125 MHz, CDCl3) δ (ppm) 166.2, 157.5, 149.5, 141.8,
138.1, 129.0, 126.4, 124.4, 122.2, 121.2, 114.7, 113.7, 102.3, 62.7, 59.8, 55.5, 14.5; MS (FAB+) m/z:
380 (M+, 100); HRMS (FAB+) m/z: calcd for C21H20N2O5 (M +): 380.1372. Found: 380.1359.

Molecules 2010, 15
8320
3.13. Typical Procedure for the reaction of enaminoester 5a with 4-nitrocinnamaldehyde 6a catalyzed
by thiourea (S, S)-1h – difluoro acid (Tables 3 and 4)
To a solution of 3a (17.7 mg, 0.10 mmol) in toluene (0.40 mL) were added thiourea (S, S)-1h
(5.4 mg, 0.010 mmol) and 0.1 M difluoroacetic acid in toluene solution (100 μL, 0.010 mmol) at
ambient temperature. To this mixture was added dropwise (50 μL/30 min) a solution of 2a (22.1 mg,
0.10 mmol) in toluene (0.50 mL) at ambient temperature. After being stirred at the same temperature for
12 h, the reaction mixture was concentrated in vacuo. The resulting residue was purified by silica gel
chromatography (hexane-ethyl acetate = 5:1) to give 7aa (32.7 mg, 86%) as a yellow oil.
(R)-Ethyl 1-(4-methoxyphenyl)-4-(4-nitrophenyl)-1,4-dihydropyridine-3-carboxylate (7aa): A yellow
1
oil; IR (ATR) 2978, 2836, 1689, 1511 cm−1; H-NMR (400 MHz, CDCl3) δ (ppm) 8.18 (d, J = 8.8 Hz,
2H), 7.64 (d, J = 1.7 Hz, 1H), 7.52 (d, J = 8.8 Hz, 2H), 7.15 (d, J = 9.0 Hz, 2H), 6.94 (d, J = 9.0 Hz,
2H), 6.39 (dd, J = 8.0 and 1.7 Hz, 1H), 4.99 (dd, J = 8.0 and 4.6 Hz, 1H), 4.74 (d, J = 4.6 Hz, 1H), 4.14-
4.00 (m, 2H), 3.83 (s, 3H), 1.15 (t, J = 7.1 Hz, 3H); 13C-NMR (125 MHz, CDCl3) δ (ppm) 167.4, 157.6,
154.6, 146.6, 138.7, 137.2, 128.7, 127.1, 123.7, 122.0, 114.9, 108.1, 103.4, 59.9, 55.6, 38.9, 14.3; MS
+
(FAB+) m/z: 380 (M+, 100); HRMS (FAB+) m/z: calcd for C21H20N2O5 (M ): 380.1372. Found:
380.1367; HPLC (CHIRALCEL AD-H, hexane-2-propanol = 80:20, flow rate 1.0 mL/min, 254 nm),
22
tr(minor) = 18.1 min, tr(major) = 22.2 min. A sample with 50% ee by HPLC analysis gave [α]D
125.2 (c 1.33, CHCl3).
=
(R)-Ethyl 1-(4-chlorophenyl)-4-(4-nitrophenyl)-1,4-dihydropyridine-3-carboxylate (7ba): By a similar
procedure described for the preparation of 7aa, 7ba was obtained from 5b and 6a as a yellow oil (78%);
IR (ATR) 2980, 2907, 1692, 1518 cm−1; 1H-NMR (400 MHz, CDCl3) δ (ppm) 8.18 (d, J = 8.8 Hz, 2H),
7.69 (d, J = 1.9 Hz, 1H), 7.50 (d, J = 8.8 Hz, 2H), 7.39 (d, J = 8.8 Hz, 2H), 7.15 (d, J = 8.8 Hz, 2H),
6.46 (dd, J = 7.8 and 1.9 Hz, 1H), 5.06 (dd, J = 7.8 and 4.6 Hz, 1H), 4.74 (d, J = 4.6 Hz, 1H), 4.15-4.05
13
(m, 2H), 1.16 (t, J = 7.1 Hz, 3H); C-NMR (125 MHz, CDCl3) δ (ppm) 167.1, 154.0, 146.6, 142.0,
137.4, 130.8, 129.9, 128.7, 126.0, 123.8, 121.0, 109.1, 105.0, 60.1, 38.8, 14.2; MS (FAB+) m/z: 384 (M+,
+
100); HRMS (FAB+) m/z: calcd for C20H17ClN2O4 (M ): 384.0877. Found: 384.0887; HPLC
(CHIRALCEL AD-H, hexane-2-propanol = 80:20, flow rate 1.0 mL/min, 254 nm), tr(minor) = 14.4 min,
tr(major) = 19.5 min. A sample with 49% ee by HPLC analysis gave [α]D25 = 91.8 (c 1.09, CHCl3).
(R)-Ethyl 1-benzyl-4-(4-nitrophenyl)-1,4-dihydropyridine-3-carboxylate (7ca): By a similar procedure
described for the preparation of 7aa, 7ca was obtained from 5c and 6a as a yellow oil (83%); IR (ATR)
1
2979, 2922, 1683, 1516 cm−1; H-NMR (400 MHz, CDCl3) δ (ppm) 8.13 (d, J = 8.8 Hz, 2H), 7.43 (d,
J = 8.8 Hz, 2H), 7.41-7.35 (m, 5H), 7.28 (s, 1H), 5.97 (d, J = 7.8 Hz, 1H), 4.86 (dd, J = 7.8 and 4.6 Hz,
1H), 4.68 (d, J = 4.6 Hz, 1H), 4.47 (s, 2H), 4.03 (m, 2H), 1.14 (t, J = 7.1 Hz, 3H); 13C- NMR (125 MHz,
CDCl3) δ (ppm) 167.5, 154.9, 146.4, 140.8, 136.7, 129.0, 128.6, 128.2, 127.7, 127.1, 123.6, 107.5,
101.3, 59.7, 57.9, 38.7, 14.3; MS (FAB+) m/z: 365 (M + H+, 100); HRMS (FAB+) m/z: calcd for
C21H21N2O4 (M + H+): 365.1501. Found: 365.1528; HPLC (CHIRALCEL AD-H, hexane/2-propanol =
85/15, flow rate 1.0 mL/min, 254 nm), tr(minor) = 14.9 min, tr(major) = 17.8 min. A sample with 45%
ee by HPLC analysis gave [α]D22 = 117.6 (c 1.14, CHCl3).

Molecules 2010, 15
8321
(R)-Ethyl 1-(4-methoxyphenyl)-2-methyl-4-(4-nitrophenyl)-1,4-dihydropyridine-3-carboxylate (7da): By
a similar procedure described for the preparation of 7aa, 7da was obtained from 5d and 6a as a yellow
1
oil (93%); IR (ATR) 2979, 2918, 1685, 1512 cm−1; H-NMR (400 MHz, CDCl3) δ (ppm) 8.18 (d,
J = 8.8 Hz, 2H), 7.50 (d, J = 8.8 Hz, 2H), 7.11 (d, J = 9.0 Hz, 2H), 6.94 (d, J = 9.0 Hz, 2H), 6.13 (d,
J = 7.6 Hz, 1H), 4.93 (dd, J = 7.6 and 5.6 Hz, 1H), 4.81 (d, J = 5.6 Hz, 1H), 4.03 (q, J = 7.1 Hz, 2H),
13
3.84 (s, 3H), 2.16 (s, 3H), 1.12 (t, J = 7.1 Hz, 3H); C-NMR (125 MHz, CDCl3) δ (ppm) 168.2 158.9,
155.8, 149.6, 146.3, 136.1, 130.6, 128.8, 128.2, 123.7, 114.8, 105.7, 99.7, 59.6, 55.5, 40.5, 18.5, 14.3;
MS (FAB+) m/z: 395 (M + H+, 100); HRMS (FAB+) m/z: calcd for C22H23N2O5 (M + H+): 395.1607.
Found: 395.1607; HPLC (CHIRALCEL AD-H, hexane-2-propanol = 80:20, flow rate 1.0 mL/min, 254
nm), tr(minor) = 7.2 min, tr(major) = 16.7 min. A sample with 66% ee by HPLC analysis gave
[α]D23 = 277.0 (c 1.20, CHCl3).
(R)-tert-Butyl
1-(4-methoxyphenyl)-2-methyl-4-(4-nitrophenyl)-1,4-dihydropyridine-3-carboxylate
(7ea): By a similar procedure described for the preparation of 7aa, 7ea was obtained from 5e and 6a as a
1
yellow oil (81%); IR (ATR) 2976, 2917, 1686, 1510 cm−1; H-NMR (400 MHz, CDCl3) δ (ppm) 8.19
(d, J = 8.8 Hz, 2H), 7.50 (d, J = 8.8 Hz, 2H), 7.10 (d, J = 8.6 Hz, 2H), 6.93 (d, J = 8.6 Hz, 2H), 6.09 (d,
J = 7.6 Hz, 1H), 4.87 (dd, J = 7.6 and 5.4 Hz, 1H), 4.78 (d, J = 5.4 Hz, 1H), 3.83 (s, 3H), 2.13 (s, 3H),
1.30 (s, 9H); 13C-NMR (125 MHz, CDCl3) δ (ppm) 167.7, 158.8, 156.1, 148.6, 146.3, 136.3, 130.5,
128.8, 128.1, 123.7, 114.7, 105.4, 101.1, 79.5, 55.5, 41.0, 28.2, 18.4; MS (FAB+) m/z: 422 (M+, 100);
HRMS (FAB+) m/z: calcd for C24H26N2O5 (M+): 422.1842. Found: 422.1852; HPLC (CHIRALCEL AD-
H, hexane-2-propanol = 90:10, flow rate 0.5 mL/min, 254 nm), tr(minor) = 13.9 min, tr(major) = 18.5 min.
A sample with 51% ee by HPLC analysis gave [α]D23 = 208.3 (c 1.30, CHCl3).
(R)-Ethyl 1-(4-methoxyphenyl)-4-(4-nitrophenyl)-2-phenyl-1,4-dihydropyridine-3-carboxylate (7fa): By
a similar procedure described for the preparation of 7aa, 7fa was obtained from 5f and 6a as a yellow
amorphous solid (85%); IR (ATR) 2980, 2917, 1674, 1511 cm−1; 1H-NMR (400 MHz, CDCl3) δ (ppm)
8.23 (d, J = 8.8 Hz, 2H), 7.67 (d, J = 8.8 Hz, 2H), 7.13-6.91 (m, 5H), 6.86 (d, J = 9.0 Hz, 2H), 6.64 (d,
J = 9.0 Hz, 2H), 6.42 (d, J = 7.6 Hz, 1H), 5.08 (dd, J = 7.6 and 5.6 Hz, 1H), 4.88 (d, J = 5.6 Hz, 1H),
13
3.75-3.68 (m, 2H), 3.70 (s, 3H), 0.70 (t, J = 7.1 Hz, 3H); C-NMR (125 MHz, CDCl3) δ (ppm) 167.7,
157.7, 155.3, 150.9, 146.5, 136.1, 135.9, 131.2, 128.6, 128.3, 127.8, 127.41, 127.40, 123.9, 114.0,
106.1, 101.4, 59.5, 55.3, 40.3, 13.5; MS (FAB+) m/z: 457 (M + H+, 100); HRMS (FAB+) m/z: calcd for
C27H25N2O5 (M + H+): 457.1763. Found: 457.1784; HPLC (CHIRALCEL AD-H, hexane-2-propanol =
93:7, flow rate 0.5 mL/min, 254 nm), tr(major) = 31.4 min, tr(minor) = 34.9 min. A sample with 61% ee
by HPLC analysis gave [α]D23 = 237.0 (c 1.12, CHCl3).
(R)-Ethyl 1-(3,4-dimethoxyphenyl)-2-methyl-4-(4-nitrophenyl)-1,4-dihydropyridine-3-carboxylate (7ga):
By a similar procedure described for the preparation of 7aa, 7ga was obtained from 5g and 6a as a
1
yellow oil (96%); IR (ATR) 2977, 2933, 1687, 1511 cm−1; H-NMR (400 MHz, CDCl3) δ (ppm) 8.19
(d, J = 8.8 Hz, 2H), 7.51 (d, J = 8.8 Hz, 2H), 6.89 (d, J = 8.6 Hz, 1H), 6.76 (dd, J = 8.6 and 2.4 Hz, 1H),
6.67 (d, J = 2.4 Hz, 1H), 6.15 (d, J = 7.6 Hz, 1H), 4.93 (dd, J = 7.6 and 5.4 Hz, 1H), 4.83 (d, J = 5.4 Hz,
1H), 4.03 (q, J = 7.1 Hz, 2H), 3.92 (s, 3H), 3.90 (s, 3H), 2.18 (s, 3H), 1.12 (t, J = 7.1 Hz, 3H); 13C-NMR
(125 MHz, CDCl3) δ (ppm) 168.2 155.8, 149.6, 149.5, 148.6, 146.3, 136.2, 130.5, 128.2, 123.7, 111.3,

Molecules 2010, 15
8322
105.6, 99.7, 59.6, 56.11, 56.07, 40.5, 18.5, 14.2; MS (FAB+) m/z: 425 (M + H+, 100); HRMS (FAB+)
m/z: calcd for C23H25N2O6 (M + H+): 425.1713. Found: 425.1725; HPLC (CHIRALCEL AD-H, hexane-
2-propanol = 80:20, flow rate 1.0 mL/min, 254 nm), tr(minor) = 10.2 min, tr(major) = 38.8 min. A
sample with 66% ee by HPLC analysis gave [α]D22 = 239.5 (c 1.18, CHCl3).
(R)-Ethyl 1-(3,4-dimethoxyphenyl)-2-methyl-4-phenyl-1,4-dihydropyridine-3-carboxylate (7gb): By a
similar procedure described for the preparation of 7aa, 7gb was obtained from 5g and 6b as a pale
1
yellow oil (61%); IR (ATR) 2977, 2932, 1686, 1510 cm−1; H-NMR (400 MHz, CDCl3) δ (ppm) 7.38-
7.29 (m, 5H), 7.21-7.16 (m, 1H), 6.87 (d, J = 8.6 Hz, 1H), 6.77 (dd, J = 8.6 and 2.4 Hz, 1H), 6.69 (d,
J = 2.4 Hz, 1H), 6.12 (d, J = 7.8 Hz, 1H), 4.98 (dd, J = 7.8 and 5.4 Hz, 1H), 4.69 (d, J = 5.4 Hz, 1H),
4.02 (q, J = 7.1 Hz, 2H), 3.91 (s, 3H), 3.89 (s, 3H), 2.16 (s, 3H), 1.13 (t, J = 7.1 Hz, 3H); 13C-NMR (125
MHz, CDCl3) δ (ppm) 168.8, 149.5, 148.6, 148.35, 148.32, 136.7, 129.6, 128.3, 127.5, 126.1, 119.9,
111.3, 111.1 107.1, 101.1, 59.3, 56.06, 56.05, 40.2, 18.4, 14.2; MS (FAB+) m/z: 380 (M + H+, 100);
HRMS (FAB+) m/z: calcd for C23H26NO5 (M + H+): 380.1862. Found: 380.1862; HPLC (CHIRALCEL
AD-H, hexane-2-propanol = 80:20, flow rate 1.0 mL/min, 254 nm), tr(minor) = 6.1 min, tr(major) = 14.5
min. A sample with 44% ee by HPLC analysis gave [α]D25 = 154.0 (c 1.23, CHCl3).
(R)-Ethyl
1-(3,4-dimethoxyphenyl)-4-(4-methoxyphenyl)-2-methyl-1,4-dihydropyridine-3-carboxylate
(7gc): By a similar procedure described for the preparation of 7aa, 7gc was obtained from 5g and 6c as a
1
pale yellow oil (56%); IR (ATR) 2977, 2929, 1685, 1508 cm−1; H-NMR (400 MHz, CDCl3) δ (ppm)
7.28 (d, J = 8.8 Hz, 2H), 6.87 (d, J = 8.6 Hz, 1H), 6.86 (d, J = 8.8 Hz, 2H), 6.76 (dd, J = 8.6 and 2.4 Hz,
1H), 6.68 (d, J = 2.4 Hz, 1H), 6.12 (d, J = 7.6 Hz, 1H), 4.96 (dd, J = 7.6 and 5.4 Hz, 1H), 4.63 (d,
J = 5.4 Hz, 1H), 4.03 (q, J = 7.1 Hz, 2H), 3.91 (s, 3H), 3.89 (s, 3H), 3.79 (s, 3H), 2.14 (s, 3H), 1.16 (t,
J = 7.1 Hz, 3H); 13C-NMR (125 MHz, CDCl3) δ (ppm) 168.9, 158.0, 149.5, 148.3, 147.9, 141.1, 136.8,
129.5, 128.5, 119.9, 113.6, 111.3, 111.1 107.2, 101.5, 59.3, 56.07, 56.05, 55.2, 39.2, 18.4, 14.2; MS
+
(FAB+) m/z: 409 (M+, 100); HRMS (FAB+) m/z: calcd for C24H27NO5 (M ): 409.1889. Found:
409.1883; HPLC (CHIRALCEL AD-H, hexane-2-propanol = 80:20, flow rate 1.0 mL/min, 254 nm),
tr(minor) = 7.6 min, tr(major) = 21.0 min. A sample with 38% ee by HPLC analysis gave [α]D25 = 136.1
(c 1.21, CHCl3).
(R)-Ethyl
1-(3,4-dimethoxyphenyl)-4-(4-fluorophenyl)-2-methyl-1,4-dihydropyridine-3-carboxylate
(7gd): By a similar procedure described for the preparation of 7aa, 7gd was obtained from 5g and 6d as
a pale yellow oil (62%); IR (ATR) 2981, 2935, 1685, 1507 cm−1; 1H-NMR (400 MHz, CDCl3) δ (ppm)
7.31 (dd, J = 8.8 and 5.9 Hz, 2H), 6.99 (dd, J = 8.8 and 8.8 Hz, 2H), 6.87 (d, J = 8.3 Hz, 1H), 6.76 (dd,
J = 8.3 and 2.4 Hz, 1H), 6.67 (d, J = 2.4 Hz, 1H), 6.12 (d, J = 7.8 Hz, 1H), 4.95 (dd, J = 7.8 and 5.4 Hz,
1H), 4.68 (d, J = 5.4 Hz, 1H), 4.03 (q, J = 7.1 Hz, 2H), 3.91 (s, 3H), 3.89 (s, 3H), 2.15 (s, 3H), 1.14 (t,
J = 7.1 Hz, 3H); 13C-NMR (125 MHz, CDCl3) δ (ppm) 168.7, 161.4 (d, 1J(C, F) = 242 Hz), 149.5, 148.4,
148.3, 144.5 (d, 4J(C, F) = 3.6 Hz), 136.6, 129.7, 128.9 (d, 3J(C, F) = 8.4 Hz), 119.9, 114.9 (d, 2J(C, F) = 21.4
Hz), 111.3, 111.0, 106.9, 101.1, 59.4, 56.09, 56.07, 39.5, 18.4, 14.2; MS (FAB+) m/z: 398 (M + H+,
100); HRMS (FAB+) m/z: calcd for C23H25FNO4 (M + H+): 398.1768. Found: 398.1751; HPLC
(CHIRALCEL AD-H, hexane-2-propanol = 80:20, flow rate 1.0 mL/min, 254 nm), tr(minor) = 6.0 min,
tr(major) = 13.1 min. A sample with 53% ee by HPLC analysis gave [α]D27 = 148.7 (c 1.73, CHCl3).

Molecules 2010, 15
(R)-Ethyl 1-(3,4-dimethoxyphenyl)-4-(3-fluorophenyl)-2-methyl-1,4-dihydropyridine-3-carboxylate
8323
(7ge): By a similar procedure described for the preparation of 7aa, 7ge was obtained from 5g and 6e as a
1
pale yellow oil (55%); IR (ATR) 2977, 2934, 1686, 1510 cm−1; H-NMR (400 MHz, CDCl3) δ (ppm)
7.28-7.23 (m, 1H), 7.13 (d, J = 7.6 Hz, 1H), 7.08-7.04 (m, 1H), 6.92-6.83 (m, 1H), 6.87 (d, J = 8.4 Hz,
1H), 6.76 (dd, J = 8.4 and 2.4 Hz, 1H), 6.68 (d, J = 2.4 Hz, 1H), 6.13 (d, J = 7.6 Hz, 1H), 4.96 (dd, J = 7.6
and 5.4 Hz, 1H), 4.70 (d, J = 5.4 Hz, 1H), 4.04 (q, J = 7.1 Hz, 2H), 3.91 (s, 3H), 3.89 (s, 3H), 2.16 (s,
3H), 1.14 (t, J = 7.1 Hz, 3H); 13C-NMR (125 MHz, CDCl3) δ (ppm) 168.6, 163.2 (d, 1J(C, F) = 243 Hz),
151.3 (d, 3J(C, F) = 6.0 Hz), 149.6, 148.7, 148.4, 136.5, 130.0, 129.5 (d, 3J(C, F) = 8.4 Hz), 122.9 (d, 4J(C, F)
2
2
= 2.4 Hz), 119.9, 114.3 (d, J(C, F) = 21.4 Hz), 112.9 (d, J(C, F) = 21.4 Hz), 111.3, 111.0, 106.5, 100.6,
59.4, 56.08, 56.07, 40.0, 18.4, 14.2; MS (FAB+) m/z: 398 (M + H+, 100); HRMS (FAB+) m/z: calcd for
C23H25FNO4 (M + H+): 398.1768. Found: 398.1748; HPLC (CHIRALCEL AD-H, hexane-2-propanol =
85:15, flow rate 1.0 mL/min, 254 nm), tr(minor) = 7.2 min, tr(major) = 13.0 min. A sample with 58% ee
by HPLC analysis gave [α]D26 = 189.7 (c 1.35, CHCl3).
(R)-Ethyl
1-(3,4-dimethoxyphenyl)-4-(2-fluorophenyl)-2-methyl-1,4-dihydropyridine-3-carboxylate
(7gf): By a similar procedure described for the preparation of 7aa, 7gf was obtained from 5g and 6f as a
1
pale yellow oil (70%); IR (ATR) 2976, 2931, 1687, 1510 cm−1; H-NMR (400 MHz, CDCl3) δ (ppm)
7.39-7.34 (m, 1H), 7.19-7.09 (m, 2H), 7.02-6.97 (m, 1H), 6.87 (d, J = 8.6 Hz, 1H), 6.77 (dd, J = 8.6 and
2.4 Hz, 1H), 6.69 (d, J = 2.4 Hz, 1H), 6.05 (d, J = 7.6 Hz, 1H), 5.03 (d, J = 5.4 Hz, 1H), 4.97 (dd, J = 7.6
and 5.4 Hz, 1H), 3.99 (q, J = 7.1 Hz, 2H), 3.91 (s, 3H), 3.89 (s, 3H), 2.20 (s, 3H), 1.07 (t, J = 7.1 Hz,
1
3H); 13C-NMR (125 MHz, CDCl3) δ (ppm) 168.6, 159.6 (d, J(C, F) = 244 Hz), 149.7, 149.5, 148.4,
2
3
136.6, 135.3 (d, J(C, F) = 14.3 Hz), 130.0, 129.76, 129.71, 127.4 (d, J(C, F) = 7.2 Hz), 124.1 (d,
4J(C, F) = 3.6 Hz), 120.0, 115.0 (d, 2J(C, F) = 22.6 Hz), 111.2 (d, 3J(C, F) = 10.7 Hz), 105.7, 98.8, 59.3, 56.06,
56.04, 33.8, 18.3, 14.2; MS (FAB+) m/z: 398 (M + H+, 100); HRMS (FAB+) m/z: calcd for C23H25FNO4
(M + H+): 398.1768. Found: 398.1761; HPLC (CHIRALCEL AD-H, hexane-2-propanol = 80:20, flow
rate 1.0 mL/min, 254 nm), tr(minor) = 6.0 min, tr(major) = 11.4 min. A sample with 44% ee by HPLC
analysis gave [α]D25 = 175.8 (c 0.985, CHCl3).
(R)-Ethyl 1-(4-chlorophenyl)-2-methyl-4-(4-nitrophenyl)-1,4-dihydropyridine-3-carboxylate (7ha): By a
similar procedure described for the preparation of 7aa, 7ha was obtained from 5h and 6a as a yellow oil
1
(78%); IR (ATR) 2980, 2901, 1691, 1517 cm−1; H-NMR (400 MHz, CDCl3) δ (ppm) 8.18
(d, J = 8.8 Hz, 2H), 7.48 (d, J = 8.6 Hz, 2H), 7.42 (d, J = 8.8 Hz, 2H), 7.14 (d, J = 8.6 Hz, 2H), 6.15 (d,
J = 7.6 Hz, 1H), 4.97 (dd, J = 7.6 and 5.4 Hz, 1H), 4.82 (d, J = 5.4 Hz, 1H), 4.03 (q, J = 7.1 Hz, 2H),
2.16 (s, 3H), 1.13 (t, J = 7.1 Hz, 3H); 13C-NMR (125 MHz, CDCl3) δ (ppm) 168.0, 155.3, 148.4, 146.4,
141.8, 133.5, 130.0, 129.9, 128.8, 128.2, 123.8, 106.3, 101.1, 59.7, 40.4, 18.6, 14.2; MS (FAB+) m/z:
398 (M+, 100); HRMS (FAB+) m/z: calcd for C21H19ClN2O4 (M +): 398.1033. Found: 398.1052; HPLC
(CHIRALCEL AD-H, hexane-2-propanol = 90:10, flow rate 1.0 mL/min, 254 nm), tr(minor) = 10.4 min,
tr(major) = 23.9 min. A sample with 38% ee by HPLC analysis gave [α]D25 = 158.0 (c 1.22, CHCl3)..
(R)-Ethyl 1-benzyl-2-methyl-4-(4-nitrophenyl)-1,4-dihydropyridine-3-carboxylate (7ia): By a similar
procedure described for the preparation of 7aa, 7ia was obtained from 5i and 6a as a yellow oil (81%);
IR (ATR) 2979, 2925, 1684, 1516 cm−1; 1H-NMR (400 MHz, CDCl3) δ (ppm) 8.13 (d, J = 8.8 Hz, 2H),

Molecules 2010, 15
8324
7.39 (d, J = 8.8 Hz, 2H), 7.38-7.31 (m, 3H), 7.22-7.20 (m, 2H), 6.02 (d, J = 7.6 Hz, 1H), 4.93 (dd,
J = 7.6 and 5.5 Hz, 1H), 4.78 (d, J = 5.5 Hz, 1H), 4.69 (d, J = 16.8 Hz, 1H), 4.59 (d, J = 16.8 Hz, 1H),
13
3.99 (q, J = 7.1 Hz, 2H), 2.46 (s, 3H), 1.09 (t, J = 7.1 Hz, 3H); C-NMR (125 MHz, CDCl3) δ (ppm)
168.3, 155.9, 149.8, 146.3, 137.6, 130.3, 129.0, 128.1, 127.7, 126.2, 123.6, 106.6, 99.3, 59.5, 53.8, 40.5,
16.0, 14.2; MS (FAB+) m/z: 378 (M+, 100); HRMS (FAB+) m/z: calcd for C22H22N2O4 (M +): 378.1580.
Found: 378.1578; HPLC (CHIRALCEL AD-H, hexane-2-propanol = 90:10, flow rate 1.0 mL/min, 254
23
nm), tr(minor) = 12.0 min, tr(major) = 15.3 min. A sample with 80% ee by HPLC analysis gave [α]D
309.8 (c 1.36, CHCl3).
=
(R)-Ethyl 1-(4-methoxybenzyl)-2-methyl-4-(4-nitrophenyl)-1,4-dihydropyridine-3-carboxylate (7ja): By
a similar procedure described for the preparation of 7aa, 7ja was obtained from 5j and 6a as a yellow oil
1
(65%); IR (ATR) 2978, 2922, 1683, 1513 cm−1; H-NMR (400 MHz, CDCl3) δ (ppm) 8.12 (d,
J = 8.1 Hz, 2H), 7.37 (d, J = 8.1 Hz, 2H), 7.13 (d, J = 8.6 Hz, 2H), 6.90 (d, J = 8.6 Hz, 2H), 6.01 (d,
J = 7.5 Hz, 1H), 4.92 (dd, J = 7.5 and 5.7 Hz, 1H), 4.77 (d, J = 5.7 Hz, 1H), 4.62 (d, J = 16.6 Hz, 1H),
4.51 (d, J = 16.6 Hz, 1H), 3.99 (q, J = 7.1 Hz, 2H), 3.82 (s, 3H), 2.46 (s, 3H), 1.09 (t, J = 7.1 Hz, 3H);
13C-NMR (125 MHz, CDCl3) δ (ppm) 168.3, 159.2, 155.9, 149.9, 146.2, 130.3, 129.5, 128.1, 127.5,
123.6, 114.3, 106.5, 99.2, 59.5, 55.3, 53.3, 40.5, 16.0, 14.2; MS (FAB+) m/z: 408 (M+, 100); HRMS
(FAB+) m/z: calcd for C23H24N2O5 (M +): 408.1685. Found: 408.1701; HPLC (CHIRALCEL AD-H,
hexane-2-propanol = 90:10, flow rate 1.0 mL/min, 254 nm), tr(minor) = 16.2 min, tr(major) = 19.3 min.
A sample with77% ee by HPLC analysis gave [α]D26 = 286.6 (c 1.20, CHCl3).
3.14. General Procedure for the reaction of 4-nitro cinnamaldehyde 6a and 4-methoxyaniline (9) with
ethyl acetoacetate (10) catalyzed by thiourea 1—Brønsted acid (Table 5)
To a mixture of thiourea 1 (0.010 mmol ) and Brønsted acid (0.010 mmol) in toluene (1.0 mL) were
added 6 (0.15 mmol) and 9 (0.10 mmol) at ambient temperature. After being stirred at the same
temperature for 30 min, 10 (0.20 mmol) was then added, and the resulting mixture was stirred at the
same temperature. The reaction mixture was concentrated in vacuo, and the resulting residue was
purified by silica gel chromatography (hexane-ethyl acetate = 5:1) to give 7da.
4. Conclusions
We have developed a Brønsted acid–bifunctional thiourea co-catalyzed asymmetric cycloaddition of
β-enamino esters and α,β-unsaturated aldehydes to afford 1,3,4-trisubstituted and 1,2,3,4-
tetrasubstituted 1,4-DHPs, which uses novel thiourea catalysts 1f and 1h as a source of chirality. With
the use of different Brønsted acids such as DFA and HBF4 with the same bifunctional thiourea, both
enantiomers of 4-substituted 1,4-dihydropyridine can be synthesized from the same starting materials.
Both the Brønsted acid and bifunctional thiourea co-catalysts are important for determining the
enantioselectivity and sense of chirality.
Acknowledgements
This work was supported in part by a Grant-in-Aid for Scientific Research (B) (Y.T.), a Grant-in-Aid
for Young Scientists (Start-up) (21890112) (T.I.) and the ‘Targeted Proteins Research Program’ from

Molecules 2010, 15
8325
the Ministry of Education, Culture, Sports, Science and Technology of Japan. We are grateful to Hikaru
Takaya and Masaharu Nakamura for their help with the determination of the catalyst’s absolute
configuration via X-ray analysis.
References and Notes
1. Ikariya, T.; Blacker, A.J. Asymmetric Transfer Hydrogenation of Ketones with Bifunctional
Transition Metal-Based Molecular Catalysts. Acc. Chem. Res. 2007, 40, 1300-1308.
2. Ikariya, T.; Murata, K.; Noyori, R. Bifunctional trans metal-based molecular catalysts for
asymmetric syntheses. Org. Biomol. Chem. 2006, 4, 393-406.
3. Shibasaki, M.; Sasai, H.; Arai, T. Asymmetric Catalysis with Heterobimet allic Compounds.
Angew. Chem., Int. Ed. 1997, 36, 1236-1256.
4. Kitamura, M.; Suga, S.; Kawai, K.; Noyori, R. Catalytic asymmetric induction. Highly
enantioselective addition of dialkylzincs to aldehydes. J. Am. Chem. Soc. 1986, 108, 6071-6072.
5. Wang, Y.; Deng, L. Asymmetric Acid-Base Bifunctional Catalysis with Organic Molecules. In
Catalytic Asymmetric Synthesis, 3rd ed.; Ojima, I., Ed.; John Wiley & Sons: Hoboken, NJ, USA,
2010; pp. 59-94.
6. Taylar, M.S.; Jacobsen, E.N. Asymmetric Catalysis by Chiral Hydrogen-Bond Donors. Angew.
Chem. Int. Ed. 2006, 45, 1520-1543.
7. Hamza, A.; Schubert, G.; Soós, T.; Pápai, I. Theoretical Studies on the Bifunctionality of Chiral
Thiourea-Based Organocatalysts: Competing Routes to C−C Bond Formation. J. Am. Chem. Soc.
2006, 128, 13151-13160.
8. Zhu, R.; Zhang, D.; Wu, J.; Liu, C. Theoretical study on the enantioselective a-amination reaction
of 1,3-dicarbonyl compounds catalyzed by a bifunctional-urea. Tetrahetron Asymmetry 2007, 18,
1655-1662
9. Takemoto, Y. Development of Chiral Thiourea Catalysts and Its Application to Asymmetric Catalytic
Reactions. Chem. Pharm. Bull. 2010, 58, 593-601.
10. Miyabe, H,; Takemoto, Y. Discovery and Application of Asymmetric Reaction by Multi-Functional
Thioureas. Bull. Chem. Soc. Jpn. 2008, 81, 785-795.
11. Takemoto, Y. Recognition and activation by ureas and thioureas: Stereoselective reactions using
ureas and thioureas as hydrogen-bonding donors. Org. Biomol. Chem. 2005, 3, 4299-4306.
12. Yamamoto, H.; Payette, J.N. Brønsted acid, H-Bond Donors, and Combined Acid systems in
Asymmetric Catalysis. In Hydrogen Bonding in Organic Synthesis, 1st ed.; Pihko, P.M., Ed.;
Wiley-VCH: Weinheim, Germany, 2009; pp. 73-140.
13. Ishihara, K.; Nakano, K. Design of an Organocatalyst for the Enantioselective Diels−Alder
Reaction with α-Acyloxyacroleins. J. Am. Chem. Soc. 2005, 127, 10504-10505.
14. Bolm, C.; Rantanen, T.; Schiffers, I.; Zani, L. Protonated Chiral Catalysts: Versatile Tools for
Asymmetric Synthesis. Angew. Chem. Int. Ed. 2005, 44, 1758-1763.
15. Nakadai, M.; Saito, S.; Yamamoto, H. Diversity-based strategy for discovery of environmentally
bengin organocatalyst: Diamine-protonic acid catalysts for asymmetric direct aldol reaction.
Tetrahedoron 2002, 58, 8167-8177.

Molecules 2010, 15
8326
16. Yoshida, K.; Inokuma, T.; Tkakasu, K.; Takemoto, Y. Brønsted Acid-Thiourea Co-catalysis:
Asymmetric Synthesis of Functionalized 1,4-Dihydropyridines from β-Enamino Esters and α,β-
Unsaturated Aldehydes. Synlett 2010, 1865-1869.
17. Singh, R.P.; Foxman, B.M.; Deng, L. Asymmetric Vinylogous Aldol Reaction of Silyloxy Furans
with a Chiral Organic Salt. J. Am. Chem. Soc. 2010, 132, 9558-9560.
18. Uyeda, C.; Jacobsen, E.N. Bifunctional Asymmetric Catalysis with Hydrogen Chloride:
Enantioselective Ring Opening of Aziridines Catalyzed by a Phosphinothiourea. Synlett 2009,
1680-1684.
19. Maiti, S.; Menendez, J.C. A Mild Protocol for the Efficient Synthesis of 5,6-Unsubstituted 1,4-
Dihydropyridines. Synlett 2009, 2249-2252.
20. Wan, J.-P.; Gan, S.-F.; Sun, G.-L.; Pan, Y.-J. Novel Regioselectivity: Three-Component Cascade
Synthesis of Unsymmetrical 1,4- and 1,2-Dihydropyridines. J. Org. Chem. 2009, 74, 2862-2865.
21. Bartoli, G.; Babiuch, K.; Bosco, M.; Carlone, A.; Galzerano, P.; Melchiorre, P.; Sambri, L.
Magnesium Perchlorate as Efficient Lewis Acid: A Simple and Convenient Route to 1,4-
Dihydropyridines. Synlett 2007, 2897-2901.
22. Sridharan, V.; Perumal, P.T.; Avendano, C.; Menendez, J.C. A new three-component domino
synthesis of 1,4-dihydropyridines. Tetrahedron 2007, 63, 4407-4413.
23. Vanden Eynde, J.J.; Mayence, A. Synthesis and Aromatization of Hantzsch 1,4-Dihydropyridines
under Microwave Irradiation. An Overview. Molecules 2003, 8, 381-391.
24. Jiang, J.; Yu, J.; Sun, X.-X.; Rao, Q.-Q.; Gong, L.-Z. Organocatalytic Asymmetric Three-
Component Cyclization of Cinnamaldehydes and Primary Amines with 1,3-Dicarbonyl
Compounds: Straightforward Access to Enantiomerically Enriched Dihydropyridines. Angew.
Chem. Int. Ed. 2008, 47, 2458-2462.
25. Moreau, J.; Duboc, A.; Hubert, C.; Hurvois, J.-P.; Renaud, J.-L. Metal-free Brønsted acids catalyzed
synthesis of functional 1,4-dihydropyridines. Tetrahedron Lett. 2007, 48, 8647-8450.
26. Kumar, A.; Marurya, R.A. Organocatalysed three-component domino synthesis of 1,4-
dihydropyridines under solvent free conditions. Tetrahedron 2008, 64, 3477-3482.
27. Parrodi, C.A.; Moreno, G.E.; Quintero, L.; Juaristi, E. Application of phosphorylated reagents
derived from N,N′-di-[(S)-α-phenylethyl]-cyclohexane-1,2-diamines in the determination of the
enantiomeric purity of chiral alcohols . Tetrahedron Asymmetry 1998, 9, 2093-2099.
28. Vachal, P.; Jacobsen, E.N. Structure-Based Analysis and Optimization of a Highly Enantioselective
Catalyst for the Strecker Reaction. J. Am. Chem. Soc. 2002, 124, 10012-10014.
29. Qian, D.; Weiran, Y.; Xumu, Z. Efficient Rhodium-Catalyzed Asymmetric Hydrogenation for the
Synthesis of a New Class of N-Aryl β-Amino Acid Derivatives. Org. Lett. 2005, 7, 5343-5345.
Sample Availability: Contact the authors.
© 2010 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article
distributed under the terms and conditions of the Creative Commons Attribution license
(http://creativecommons.org/licenses/by/3.0/).