Br?nsted acid-thiourea co-catalysis: Asymmetric synthesis of functionalized 1,4-dihydropyridines from β-enamino esters and α,β-unsaturated aldehydes

Article abstract of DOI:10.1055/s-0030-1258090

A Br?nsted acid and a novel thiourea derivative co-catalyze the addition of β-enamino esters to α,β-unsaturated aldehydes leading to functionalized 1,4-dihydropyridines with moderate to good enantioselectivity. A regioselective synthesis of 1,2-dihydropyridines from α,β-unsaturated aldehydes is also described. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0030-1258090

LETTER
1865
Brønsted Acid–Thiourea Co-catalysis: Asymmetric Synthesis of Function-
alized 1,4-Dihydropyridines from b-Enamino Esters and a,b-Unsaturated
Aldehydes
A
symmetric Synth
o
esis of Funct
h
ionalized 1,4
z
-Dihydropy
o
ridines Yoshida, Tsubasa Inokuma, Kiyosei Takasu, Yoshiji Takemoto*
Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan
Fax +81(75)7534569; E-mail: takemoto@pharm.kyoto-u.ac.jp
Received 12 April 2010
OH
O
O
O
Abstract: A Brønsted acid and a novel thiourea derivative co-cata-
lyze the addition of b-enamino esters to a,b-unsaturated aldehydes
leading to functionalized 1,4-dihydropyridines with moderate to
good enantioselectivity. A regioselective synthesis of 1,2-dihydro-
pyridines from a,b-unsaturated aldehydes is also described.
R3
OR4
R1
R3
OR4
R2
N
R1
R2
N
H
O
O
– H2O
Key words: asymmetric organocatalysis, Brønsted acid, thiourea,
1,4-dihydropyridines, b-enamino esters, a,b-unsaturated aldehydes
(a)
R2
R2
H
CO2R4
R3
R1NH2
N
R1
1,4-Dihydropyridines (1,4-DHP) and their derivatives are
important bioactive molecules in the field of drugs and
pharmaceuticals. These compounds are well-known calci-
um channel blockers that are used for the treatment of
hypertension1 and have a broad range of other pharmaco-
logical activities such as HIV protease inhibition,2 non-
competitive inhibition of topoisomerase I,3 MDR
reversal,4 and radioprotection.5 These examples clearly
indicate the noteworthy potential of novel dihydropyri-
dine derivatives as seeds for valuable drug candidates. In
addition, 1,4-DHP can be used as effective hydrogen
sources in the field of synthetic chemistry.6
O
(b)
R3
OR4
– H2O
O
R1
O
R1
NH
R2
H
NH
O
R3
OR4
CHO
R3
OR4
R2
Scheme 1 Possible synthetic routes to 1,4-DHP
been elaborated further. Herein, we describe Brønsted
acid–thiourea co-catalyzed asymmetric cycloadditions of
b-enamino esters and a,b-unsaturated aldehydes, which
afford functionalized 5,6-unsubstituted 1,4-DHP with
enantioselectivities of up to 80% ee.
Due to the importance of 1,4-DHP derivatives from phar-
maceutical and synthetic points of view, various methods
have been reported for their preparation.7 The best known
procedure for the preparation of symmetrical 1,4-DHP is
the classical Hantzsch method,8 but N-substituted DHP
that do not bear substituents on the 5- and/or 6-positions
cannot be synthesized with this protocol. Recently, syn-
thetic methods leading to such unsymmetrical DHP have
been reported.9 However, there have been only a few re-
ports on the catalytic enantioselective synthesis of 1,4-
DHP.10,11 These methods can be classified into two syn-
thetic pathways, as shown in Scheme 1.
The key to success for this strategy is how to activate b-
enamino esters as nucleophiles by aminothiourea 1, which
efficiently deprotonated b-keto esters in the asymmetric
reaction reported previously.12 Our working hypothesis is
shown in Scheme 2. When thiourea 1 and a Brønsted acid
are mixed in a 1:1 ratio, an ammonium salt complex A13
would be formed, in which the conjugate base is anchored
to the thiourea moiety by hydrogen bonds.14 This complex
can be considered as a new bifunctional catalyst; a,b-un-
saturated aldehyde 3 and enamino ester 2 should be acti-
vated by the ammonium proton and the conjugate base
(X–), respectively. As a result, 1,4-conjugated addition
would be promoted in a chiral environment to furnish the
desired 1,4-DHP 4, after subsequent intramolecular cy-
clization and dehydration. The merit of this strategy is that
the acidity and basicity of complex A can be tuned by ap-
propriate selection of the acid (HX).
Gong et al. reported the highly enantioselective three-
component cyclization of cinnamaldehydes, arylamines,
and 1,3-dicarbonyl compounds catalyzed by a chiral phos-
phoric acid via pathway a.10 However, the substituent (R3)
of 1,3-dicarbonyl compounds is limited to methyl or ethyl.
So far, only a single asymmetric example that used the b-
enamino esters (route b) has been reported by Renaud et
al., who used a chiral phosphoric acid catalyst to obtain
the product in 50% ee.11 This preliminary result has not
SYNLETT 2010, No. 12, pp 1865–1869
x
x
.x
x
.2
0
1
0
Advanced online publication: 11.06.2010
DOI: 10.1055/s-0030-1258090; Art ID: U02810ST
© Georg Thieme Verlag Stuttgart · New York

1866
K. Yoshida et. al.
LETTER
Table 1 Initial Screening of Reaction Conditionsa
S
R2
S
Ar
N
H
N
H
CO2Et
Ar
N
R
R
N
H
N
R
N
H
thiourea 1
H
R1
N
CO2Et
N
(10 mol%)
R
X
H
R1
4aa
+
thiourea 1
base
acid
acid
(10 mol%)
2a R1 = 4-MeOC6H4
complex A
+
+
2, 3
toluene, r.t.
HX
O
CO2Et
R2
3a R2 = 4-O2NC6H4
H
S
N
R2
N
R1
Ar
N
H
R1
R3
R
R
O
HN
O
H
N
5aa
R4O
X
H
Entry Brønsted Acid– Time Yield ee of 4aa Yield ee of 5aa
2
3
Thiourea
(h) of 4aa (%)c
of 5aa (%)c
O
R1
(%)b
(%)b
H
N
O
R3
1
(R,R)-1a
48
0
0
R2
H
R2
2
DFA
24 (35)d
(65)d
0
R4O
thiourea 1
HX
3
DFA–(R,R)-1a 48
0
R2
4
DFA–(R,R)-1b 24 59
28 (S)
39 (R)
28 (R)
78 (R)
50 (R)
28
17
18
trace
0
2
0
1
R1
CO2R4
R3
O
HN
5
DFA–(S,S)-1c
TFA–(S,S)-1c
24 72
24 71
R4O
R3
– H2O
N
R1
6
CHO
R2
4
7
AcOH–(S,S)-1c 48 11
DFA–(S,S)-1c
12f 86
DFA–(R,R)-1dg 12f
8e
9e
Scheme 2 A mechanistic proposal for the reaction of b-enamino
0
51
12
S
a The reactions were carried out with 2a (0.1 mmol, E/Z = <5:95),
3a (0.1 mmol), thiourea (10 mol%), and Brønsted acid (10 mol%) in
toluene (1 mL) at r.t.
Ar
S
N
H
N
H
Ar
Ar
HN
X
b Isolated yield.
N
H
N
H
R
R
N
c Determined by HPLC.
Y
d Conversion as determined by 1H NMR.
e Slow addition of 2a (0.01 mmol/30 min).
f Stirred for 12 h after completion of the addition of 2a.
g Conditions: 20 mol% thiourea 1d was used.
1a
1b X = Y = H
1e X = OMe, Y = H
S
S
Ar
N
H
N
H
N
H
N
H
phile. We then examined N-arylthioureas 1b and 1c,
whose aniline moieties are weaker bases than the N,N-
dimethylamine moiety of 1a, in the presence of several
carboxylic acids. As expected, the use of 1b or 1c with
DFA in a 1:1 ratio provided 1,4-DHP 4aa in 59% or 72%
yield together with 1,2-DHP 5aa as a minor product (en-
tries 4 and 5). In both cases, moderate enantioselectivities
were observed for 4aa (28% and 39% ee). The use of TFA
instead of DFA with 1c decreased the enantioselectivity to
28% ee, while 78% ee was obtained with AcOH, albeit
with very low yield (entries 6 and 7). Unfortunately, we
could not improve both the chemical yield and enantiose-
lectivity despite screening a variety of conditions (solvent,
temperature, and additives).17 Finally, we found that the
slow addition of b-enamino ester 2a to a mixture of 3a,
DFA, and 1c improved the chemo- (4aa/5aa) and enantio-
selectivity (86%, 50% ee; entry 8). Notably, 1d, which has
a hydroxy group in place of the amine, exclusively gave
5aa in 51% yield with low enantioselectivity (12% ee) un-
O
HN
X
HO
Y
1c X = F, Y = OMe
1d
1f X = Y = OMe
Ar = 3,5-(CF3)2C6H3
1g X = F, Y = Oi-Pr
Figure 1 Structures of thiourea catalysts employed
The reaction of b-enamino ester 2a (E/Z = <5:95)15 and
aldehyde 3a was carried out with various ratios of HX and
thioureas 1a–d16 (Figure 1, Table 1). We first investigated
the reaction in the presence of 1a alone, but only recov-
ered the starting material (entry 1). Although the presence
of 10 mol% difluoroacetic acid (DFA) effectively promot-
ed the reaction even at ambient temperature to give 1,4-
DHP 4aa and 1,2-DHP 5aa in a ratio of 35:65, the same
reaction with a 1:1 mixture of 1a and DFA gave none of
the desired products (entries 2 and 3). This means that the
conjugate acid of 1a is too weak to activate the electro-
Synlett 2010, No. 12, 1865–1869 © Thieme Stuttgart · New York

LETTER
Asymmetric Synthesis of Functionalized 1,4-Dihydropyridines
1867
Table 2 Catalyst Screeninga
der otherwise the same conditions (entry 9). This is the
first example of a catalytic asymmetric synthesis of a 1,2-
DHP.
H
R1
N
CO2Et
thiourea 1
R3
Next, we screened the substituent of the aniline moiety of
the thiourea (Table 2). When 2a was slowly added to a re-
action mixture of 3a, 1b, and DFA at room temperature,
both the chemical yield and enantioselectivity were pre-
dictably improved but lower than when 1c was used (entry
1). The use of b-enamino ester 2b resulted in a slight in-
crease in enantioselectivity (61% ee; entry 2).
(10 mol%)
R2
N
2a R1 = 4-MeOC6H4, R3 = H
2b R1 = 4-MeOC6H4, R3 = Me
DFA
(10 mol%)
CO2Et
+
toluene, r.t., 12 h
O
R1
4aa
R2
H
3a R2 = 4-O2NC6H4
Therefore, we evaluated thioureas 1e–g with both 2a and
2b, respectively. We found that thiourea 1g gave the best
results in terms of ee among the synthesized thiourea cat-
alysts (66% ee; entries 3–7). With this result, we estab-
lished that, optimally, the reaction should be carried out in
the presence of DFA and 1g and with the slow addition of
b-enamino esters.
Entry Thiourea
Enamino Product
Ester
Yield (%)b ee (%)c
1
2
3
4
5
6
7
(R,R)-1b
(S,S)-1c
(R,R)-1e
(S,S)-1f
(S,S)-1f
(S,S)-1g
(S,S)-1g
2a
2b
2a
2a
2b
2a
2b
4aa
4ba
4aa
4aa
4ba
4aa
4ba
86
84
47
91
65
92
93
42 (S)
61 (R)
41 (S)
55 (R)
56 (R)
50 (R)
66 (R)
With the optimized conditions in hand we examined sev-
eral substrates (2c–k and 3a–f, Table 3).18 No great differ-
ence was found between the use of tert-butyl ester and
ethyl ester (entry 1), but the use of enaminone 2d derived
from diketone led to low enantioselectivity (entry 2). A
phenyl group at the b-position (2e, R3 = Ph) also gave 4ea
with similarly good enantioselectivity, as was observed
for 2b (R3 = Me, entry 3). Moderate enantioselectivities
were observed in the reaction of 2f with various a,b-unsat-
urated aldehydes 3a–f with both electron-rich and -poor
a Reaction conditions: slow addition (0.01 mmol/30 min) of 2a (0.1
mmol, E/Z = <5:95) or 2b (0.1 mmol, E/Z = <5:95) to a mixture of 3a
(0.1 mmol), thiourea (10 mol%), and DFA (10 mol%) in toluene (1
mL) at r.t. The mixture was stirred for an additional 12 h after com-
aromatic groups (entry 4–9). In these cases, the removal pletion of the addition.
b Isolated yield.
of an electron-withdrawing substituent or introduction of
an electron-donating group led to a decrease in enantiose-
c Determined by HPLC.
lectivity (entries 5 and 6). In addition, we examined the
selectivities (entries 13 and 14). These results indicate that
reaction of 3a with b-enamino esters 2g–k with different
N-substituents (entries 10–14). b-Enamino ester 2g and
2h with a para-chlorophenyl group on nitrogen led to a
decrease in enantioselectivity (entries 10 and 11). On the
other hand, the reaction of b-enamino esters with a benzyl
group at the nitrogen and a methyl group at the b-position
afforded the corresponding 1,4-DHP with good enantio-
the substituents on nitrogen and at the b-position of the b-
enamino ester might be the most important factors in this
reaction. The absolute configuration of the products 4 was
determined by comparison of the specific rotation of 4ba
to that described in the literature.10
Table 3 Substrate Scopea
thiourea 1g
(10 mol%)
R2
DFA
COR4
H
O
(10 mol%)
CHO
R1
N
R4
+
R2
toluene, r.t., 12 h
N
R3
3
R3
R1
2
4
Entry
Emanino Esters
a,b-Unsaturated Aldehydes
Product
Yield (%)b ee (%)c
2
R1
R3
Me
H
R4
3
R2
4
1
2
3
4
2c
2d
2e
2f
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
3,4-(MeO)2C6H3
Ot-Bu
Ph
3a
3a
3a
3a
4-O2NC6H4
4-O2NC6H4
4-O2NC6H4
4-O2NC6H4
4ca
4da
4ea
4fa
81
76
85
96
51
18
61
66
Ph
Me
OEt
OEt
Synlett 2010, No. 12, 1865–1869 © Thieme Stuttgart · New York

1868
K. Yoshida et. al.
LETTER
Table 3 Substrate Scopea (continued)
thiourea 1g
(10 mol%)
R2
N
DFA
(10 mol%)
COR4
R3
H
O
CHO
R1
N
R4
+
R2
toluene, r.t., 12 h
3
R3
R1
2
4
Entry
Emanino Esters
a,b-Unsaturated Aldehydes
Product
Yield (%)b ee (%)c
2
R1
R3
R4
3
R2
4
5
6
2f
2f
2f
2f
2f
2g
2h
2id
2j
2k
3,4-(MeO)2C6H3
3,4-(MeO)2C6H3
3,4-(MeO)2C6H3
3,4-(MeO)2C6H3
3,4-(MeO)2C6H3
4-ClC6H4
Me
Me
Me
Me
Me
H
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
3b
3c
3d
3e
3f
Ph
4fb
4fc
4fd
4fe
4ff
61
56
62
55
70
78
78
83
81
65
44
38
53
58
44
49
38
45
80
77
4-MeOC6H4
4-FC6H4
3-FC6H4
2-FC6H4
4-O2NC6H4
4-O2NC6H4
4-O2NC6H4
4-O2NC6H4
4-O2NC6H4
7
8
9
10
11
12
13
14
3a
3a
3a
3a
3a
4ga
4ha
4ia
4ja
4ka
4-ClC6H4
Me
H
Bn
Bn
Me
Me
4-MeOC6H4CH2
a Reaction conditions: slow addition (0.01 mmol/30 min) of enamino esters 2 (0.1 mmol, E/Z = <5:95) to a mixture of a,b-unsaturated aldehydes
3 (0.1 mmol), thiourea (S,S)-1g (10 mol%), and DFA (10 mol%) in toluene (1 mL) at r.t The mixture was stirred for an additional 12 h after
completion of the addition.
b Isolated yield.
c Determined by HPLC.
d The ratio of E/Z of 2i was 33:67.
(2) (a) Hilgeroth, A. Mini-Rev. Med. Chem. 2002, 2, 235.
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In conclusion, we have developed a Brønsted acid–
thiourea co-catalyzed asymmetric cycloaddition of b-
enamino esters and a,b-unsaturated aldehydes to afford
1,3,4-trisubstituted and 1,2,3,4-tetrasubstituted 1,4-DHP,
using novel thiourea catalyst 1g as a source of chirality.
Acknowledgment
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 the Ministry of Education, Culture, Sports, Science and Tech-
nology of Japan. We are grateful to Prof. Hikaru Takaya and Prof.
Masaharu Nakamura for their help with the determination of the ca-
talyst’s absolute configuration via X-ray analysis.
References and Notes
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Synlett 2010, No. 12, 1865–1869 © Thieme Stuttgart · New York

LETTER
Asymmetric Synthesis of Functionalized 1,4-Dihydropyridines
1869
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(17) In addition to toluene, we tested a chlorinated solvent
(CH2Cl2) and ethers (THF, Et2O). Lower temperature (0 °C)
led to a decrease in yield (<5%), while higher temperatures
(50 °C) and catalyst loading (20 mol%) led to an increased
yield but lower ee (28%, 55% ee). The addition of molecular
sieves (3 Å, 4 Å) inhibited the reaction, while other additives
(NaSO4, MgSO4) led to a decrease in enantioselectivity
without improving the yield.
(18) Typical Procedure for the Reaction of 2j and 3a
Catalyzed by Thiourea 1g – DFA
(11) Moreau, J.; Duboc, A.; Hubert, C.; Hurvois, J.-P.; Renaud,
To a solution of cinnamaldehyde (3a, 17.7 mg, 0.10 mmol)
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mmol) and 0.1 M difluoroacetic acid in toluene solution (100
mL, 0.010 mmol) at r.t. To this mixture was added dropwise
(50 mL/30 min) a solution of 2j (22.0 mg, 0.10 mmol) in
toluene (0.50 mL) at r.t. 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–EtOAc = 5:1) to give 4ja (30.8
mg, 81%) as a yellow oil.
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(15) When 2a (E/Z = 25:75) was reacted with 3a in the presence
of DFA-(S,S)-1c, 4aa was obtained in 50% ee (compared
to entry 8 in Table 1). Therefore we concluded that the
stereochemistry of the enamino esters would not effect to the
enantioselectivities.
(R)-Ethyl 1-Benzyl-2-methyl-4-(4-nitrophenyl)-1,4-
dihydropyridine-3-carboxylate (4ja)
IR (ATR): 2979, 2925, 1684, 1516 cm–1. 1H NMR (400
MHz, CDCl3): d = 8.13 (d, J = 8.8 Hz, 2 H), 7.39 (d, J = 8.8
Hz, 2 H), 7.38–7.31 (m, 3 H), 7.22–7.20 (m, 2 H), 6.02 (d,
J = 7.6 Hz, 1 H), 4.93 (dd, J = 7.6, 5.5 Hz, 1 H), 4.78 (d,
J = 5.5 Hz, 1 H), 4.69 (d, J = 16.8 Hz, 1 H), 4.59 (d, J = 16.8
Hz, 1 H), 3.99 (q, J = 7.1 Hz, 2 H), 2.46 (s, 3 H), 1.09 (t,
J = 7.1 Hz, 3 H) ppm. 13C NMR (125 MHz, CDCl3): d =
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 (100) [M+]. HRMS (FAB+):
m/z calcd for C22H22N2O4 [M+]: 378.1580; found: 378.1578.
HPLC (CHIRALCEL AD-H, hexane–2-PrOH = 90:10, flow
rate 1.0 mL/min, 254 nm): tr(minor) = 12.0 min, tr(major) =
15.3 min. A sample with 80% ee gave [a]D23 +309.8 (c 1.36,
CHCl3).
(16) The absolute configuration of the thiourea catalysts
described has been assigned based on the known
Synlett 2010, No. 12, 1865–1869 © Thieme Stuttgart · New York

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