Highly enantioselective Biginelli reaction promoted by chiral bifunctional primary amine-thiourea catalysts: Asymmetric synthesis of dihydropyrimidines

Article abstract of DOI:10.1002/adsc.200900597

The diastereospecific formation of dihydropyrimidines (DHPMs) has been achieved in moderate to high yields with up to 99% ee by a Biginelli reaction. The reaction was performed by using a combined catalyst consisting of a chiral bifunctional primary amine

Full text of DOI:10.1002/adsc.200900597

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DOI: 10.1002/adsc.200900597
Highly Enantioselective Biginelli Reaction Promoted by Chiral
Bifunctional Primary Amine-Thiourea Catalysts: Asymmetric
Synthesis of Dihydropyrimidines
Yangyun Wang,a Haitao Yang,a Jipan Yu,a Zhiwei Miao,a,b,* and Ruyu Chena,*
a
State Key Laboratory and Institute of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, Peopleꢀs Republic
of China
Fax : (+86)-22-2350-2351; e-mail: miaozhiwei@nankai.edu.cn
Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology (Ministry of Education), Tsinghua University,
b
Beijing 100084, Peopleꢀs Republic of China
Received: August 30, 2009; Revised: November 2, 2009; Published online: December 2, 2009
Dedicated to Prof. Ruyu Chen on the occasion of her 90th birthday.
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200900597.
Abstract: The diastereospecific formation of dihy-
dropyrimidines (DHPMs) has been achieved in
moderate to high yields with up to 99% ee by a Bi-
ginelli reaction. The reaction was performed by
using a combined catalyst consisting of a chiral bi-
functional primary amine-thiourea 9f and a Brønst-
ed acid with tert-butylammonium trifluoroacetate
(t-BuNH2·TFA) as additive in dichloromethane at
room temperature. The possible mechanism for the
reaction has been proposed to explain the origin of
the activation and the asymmetric induction.
agent (Figure 1).[5] Furthermore, some marine natural
products containing the dihydropyrimidine-5-carbox-
ylate core have been isolated and exhibited interest-
ing biological activities.[6]
Compounds containing the DHPM moiety are in-
herently asymmetric molecules, and the influence of
the absolute configuration at the stereogenic center at
C-4 on the biological activity has been extensively in-
vestigated. Different enantiomers exhibit different or
even opposite biological activities.[7] The original Bigi-
nelli reaction does not have any enantiocontrol factor
during formation of the new stereocenter. The proce-
dures for manufacturing optically pure DHPMs
mainly focus on resolution and chiral auxiliary-assist-
ed asymmetric synthesis.[8] Compared with the two
Keywords: Biginelli reaction; enantioselectivity; or-
ganocatalysis; primary amino-thiourea catalyst
The synthesis of functionalized 3,4-dihydropyrimidin-
2(1H)-ones (DHPMs) (1) via the Biginelli reaction, a
three-component condensation reaction between an
aldehyde, a urea or a thiourea, and an easily enoliza-
ble carbonyl compound which was originally de-
scribed by the Italian chemist Pietro Biginelli in
1893.[1] The medicinal importance of DHPMs has
been recognized for many decades and many com-
pounds exhibit antiviral, antitumor, antibacterial, and
anti-inflammatory properties.[2] Nitractin (2) was first
reported in the 1960s as an agent against the tracho-
ma group of viruses.[3] Monastrol (3) is currently
known as a specific inhibitor of mitotic kinesis Eg5
and is considered as lead compound to develop new
anticancer drugs.[4] Also, (R)-SQ32926 (4) has been
identified as a potent orally active antihypertensive Figure 1. Examples of biologically active DHPMs.
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Table 1. Screening catalysts for the asymmetric Biginelli re-
kinds of asymmetric synthesis methods, the catalytic
asymmetric Biginelli reaction is definitely the most
straightforward approach to access optically active
DHPMs. Gong reported the first organocatalytic
highly enantioselective Biginelli reaction using a H8-
Binol-based chiral phosphoric acids as catalyst.[9] Feng
also reported an enantioselective Biginelli reaction
catalyzed by a trans-4-hydroxyproline-derived secon-
dary amine and a Brønsted acid as the combined cata-
lyst.[10] Recently, Zhao and Wang reported the asym-
metric Biginelli reaction catalyzed by substituted 5-
action.[a]
(pyrrolidin-2-yl)tetrazoles.[11] Indeed, urea
ACTHNUGRTENUNG(thiourea)-
based organocatalysts have been widely used in asym-
metric catalysis.[12] Herein we wish to report the de-
velopment of conditions for performing highly enan-
tioselective Biginelli condensation reactions catalyzed
by a chiral bifunctional primary amine-thiourea cata-
lyst in the presence of a Brønsted acid as a combined
catalyst.
Chiral urea and thiourea derivatives have proven to
be extraordinarily useful as catalysts for the enantio-
selective activation of imine and carbonyl derivatives
toward nucleophilic addition.[13] Carbohydrates are in
general very attractive scaffolds because of their
availability and well-defined stereocenters. Thus a
novel saccharide scaffold was employed in asymmet-
ric reactions. Ma has reported that thiourea catalysts
possessing a neighboring primary amine function are
essential for good reactivity and enantioselectivity of
the Michael addition reaction of aromatic ketones to
nitroolefins.[14] However, a bifunctional thiourea cata-
lyst has never been employed in the Biginelli reac-
tion.
Entry
Catalyst
Yield [%][b]
ee [%][c]
We initially investigated the catalytic asymmetric
Biginelli reaction of urea (5), benzaldehyde (6) and
ethyl acetoacetate (7) with bifunctional thiourea cata-
lyst (9) and trifluoroacetic acid (TFA) in CH2Cl2 at
room temperature. Catalyst 9a could catalyze this re-
action to provide the desired product DHPM in 30%
yield, but the enantioselectivity was rather poor
(Table 1, entry 1). Moreover, the N-Bn-protected
1
2
3
4
9a
9b
9c
9d
9e
9f
9f
30
13
19
27
40
60
61
<3
<3
<3
<3
9
5
6
15
18
7e)
[a]
The reaction was carried out on a 0.5 mmol scale and the
ratio of 5/6/7 is 1/1.5/3.
Isolated yield based on the urea.
Determined by HPLC (Chiralcel OD-H).
TFA=trifluoroacetic acid.
thioACHTUNGTRENNUNGurea catalyst 9b, the pyridine-substituted thiourea
catalyst 9c, and 2-phenylethanol-thiourea catalyst 9d,
all failed to catalyze the asymmetric Biginelli reaction
(Table 1, entries 2–4). Next, we explored 3,5-bis(tri-
fluoromethyl)phenylthiourea 9e as catalyst and found
that this reaction can work effectively to provide
DHPM in 40% yield and 9% ee. This result suggested
[b]
[c]
[d]
[e]
10 mol% of catalyst 9f was used.
that a primary amine-thiourea structure is essential to TsOH, LiBr, InBr3, BF3·OEt2, FeCl3, and so on.[15] In
effect the Biginelli reaction. Consequently, we found order to improve the efficiency, various acids com-
that gluco-2-aminocyclohexylthiourea 9f could cata- bined with 9f were then employed to catalyze this re-
lyze this reaction and produce the DHPM in 60% action. Compared with TFA, organic and inorganic
yield and 15% ee. Furthermore, increasing the loading acids can promote the reaction smoothly. For example
amount of catalyst from 5 to 10% did not affect the HAc, HCOOH, HCl and H3PO4 combined with 9f
yield, but resulted in a higher ee (Table 1, entry 7).
were employed to catalyze the reaction and get
Several Lewis and Brønsted acids were reported to DHPMs in moderate ee (Table 2, entries 2–5). Re-
catalyze the Biginelli reaction such as HCl, H2SO4, cently, Feng reported that different substituted benzo-
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Table 2. Investigation of the Bønsted acid-catalyzed asym-
Table 3. Optimization of solvent for the asymmetric Biginelli
metric Biginelli reaction.[a]
reaction.[a]
Yield [%][b] ee [%][c]
Entry
Solvent
Yield [%][c]
ee (%)[d]
Entry Acid
1
2
3
4
5
6
7
8
CH2Cl2
THF
DMF
1,4-Dioxane
CHCl3
Toluene
Acetone
CH3CN
Petroleum ether
CH3OH
CH2Cl2
90
trace
35
65
80
70
75
65
60
63
n.d.[e]
2
1
2
3
4
5
6
7
TFA
HAc
60
20
25
10
15
26
30
15
60
63
80
60
53
53
63
32
HCOOH
HCl
H3PO4
Benzoic acid
p-TSA
2
52
49
53
40
50
66
94
8
2,4,6-Trichlorobenzoic acid 90
2,4,6-Trichlorobenzoic acid 58
9[d]
9
10
35
93
[a]
11[f]
The reaction was carried out on a 0.5 mmol scale and the
ratio of 5/6/7 is 1/1.5/3.
Isolated yield based on the urea.
Determined by HPLC (Chiralcel OD-H).
Catalyst 9e was employed in the reaction.
[a]
[b]
[c]
[d]
Reagents and conditions: after stirring a solution of acid
(10 mol%), benzaldehyde (0.75 mmol), urea (0.5 mmol),
in 2 mL of dry solvent at 258C for 1 h, catalyst 9f
(5 mol%) and ethyl acetoacetate (1.5 mmol) were added
sequentially.
TCBA=2,4,6-trichlorobenzoic acid.
Isolated yield based on urea.
Determined by HPLC (Chiralcel OD-H).
n.d.=not determined.
10 mol% t-BuNH2·TFA was added as additive.
[b]
[c]
[d]
[e]
[f]
ic acids were favorable in terms of reactivity and
enantioselectivity of the Biginelli reaction.[10] We
screened benzoic acid, p-TSA and 2,4,6-trichloroben-
zoic acid, the results indicated that the electron-with-
drawing-substituted 2,4,6-trichlorobenzoic acid dem-
onstrated the advantage of control of enantioselectivi-
ty in this reaction (Table 2, entries 6–8). When cata-
lyst 9e was employed in the presence of 2,4,6- ganic amine salts were reported have the effect to im-
trichlorobenzoic acid, the reaction achieved 58% prove the reactivity and enantioselectivity of the Bigi-
yield with 32% ee (Table 2, entry 9).
nelli reaction.[10] In our investigation, after screening
ACHTUNGTRENNUNG
To optimize the reaction conditions further, the sol- the acidic component, it was found that t-BuNH2·TFA
vent effect was investigated with thiourea catalyst 9f combined with 2,4,6-trichlorbenzoic acid gave superi-
combined with 2,4,6-trichlorobenzoic acid, and the or results in terms of reactivity and enantioselectivity
best result was obtained in CH2Cl2 (Table 3, entry 1). (93% yield, 94% ee, Table 3, entry 11). There was no
The reaction cannot work in THF (Table 3, entry 2). desired DHPM product obtained when only t-
When the reaction was performed in DMF or 1,4-di- BuNH2·TFA was employed in this reaction without
oxane, a very poor ee value was obtained even with 2,4,6-trichlorbenzoic acid. Thus, the optimal reaction
increasing the catalyst loading from 5 to 10 mol% conditions for this transformation were determined to
(Table 3, entries 3 and 4). Similar results were ob- be 0.5 mmol urea, 1.5 equivalents of aldehyde,
tained when the reaction was performed in CHCl3, 3 equivalents of ethyl acetoacetate, 5 mol% of 9f
toluene, acetone and CH3CN (Table 3, entries 5–8). combined with 10 mol% of 2,4,6-trichlorbenzoic acid
Interestingly, although the solubility of urea and cata- containing 10 mol% of t-BuNH2·TFA in CH2Cl2 as
lyst was very low in petroleum ether, the reaction still solvent at room temperature.
worked very well and furnished the product in 60%
Based on the above optimization efforts, the sub-
yield with 50% ee (Table 3, entry 9). When using strate scope of this reaction was investigated
methanol as solvent a low yield was gained even with (Table 4). In general, all the examined substrates
a prolonged reaction time, although the ee was com- could furnish the desired products in good yields and
parable to that of CH2Cl2 (Table 3, entry 10).
with moderate-to-good enantioselectivities. The scope
To further improve the reactivity and enantioselec- of the aldehyde component was first investigated by
tivity, the effect of additives was investigated. The or- reaction with urea (5a) and ethyl acetoacetate (7). A
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Yangyun Wang et al.
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Table 4. Enantioselective Biginelli reaction catalyzed by bifunctional primary amine-thiourea catalysts.[a]
Entry
8
R
X
Yield [%][b]
ee [%][c]
Configuration[d]
1
2
3
4
5
6
7
8
9
8a
8b
8c
8d
8e
8f
8g
8h
8i
C6H5
4-F-C6H4
O
O
O
O
O
O
O
O
O
93
85
72
77
83
81
88
78
51
94
93
>99
74
89
67
80
>99
15
S
S
S
S
S
S
S
S
S
4-Cl-C6H4
4-Br-C6H4
4-Me-C6H4
4-MeO-C6H4
3-F-C6H4
3-Me-C6H4
CH3CH2CH2
10
8j
O
89
95
R
11
8k
8l
8m
C6H5
3-F-C6H4
C6H5
S
S
O
91
86
90
93
87
92
S
S
R
12
13[e]
[a]
Reagents and conditions: after stirring a solution of TCBA (10 mol%), benzaldehyde (0.75 mmol), urea (0.5 mmol), and t-
BuNH2·TFA (10 mol%) in 2 mL of CH2Cl2 at 258C for 1 h, catalyst 9f (5 mol%) and ethyl acetoacetate (1.5 mmol) were
added sequentially.
[b]
[c]
[d]
[e]
Isolated yield based on urea or thiourea.
Determined by HPLC (Chiralcel OD-H or AD-H or AS-H).
The absolute configuration was determined by comparison of the optical rotation with the literature.[16]
Catalyst 9g (5 mol%) was employed in the reaction.
variety of aromatic aldehydes bearing both electron-
In order to determine the structure of the products,
donating and electron-withdraw groups underwent a single crystal X-ray diffraction study of 8a was per-
the reaction to afford high enantioselectivities ranging formed.[17] The molecular structure of 8a is shown in
from 67 to 99% ee (Table 4, entries1–8). Both the re-
actions of meta-substituted benzaldehydes and para-
substituted benzaldehydes proceeded in high yields,
meta-methylbenzaldehyde and para-chlorobenzalde-
hyde resulted in excellent enantioselectivities (>99%
ee). An aliphatic aldehyde was found to be less reac-
tive and afforded a low enantioselectivity of 15% ee
(Table 4, entry 9). The existence of a hydrogen bond
between a furan ring and the primary amine-thiourea
structure is important: when furanaldehyde was em-
ployed in this reaction, the absolute configuration of
the product changed to R (Table 4, entry 10). The Bi-
ginelli reactions of thiourea (5b) with various benzal-
dehydes and b-keto esters were carried out to give
the corresponding DHPMs with up to 93% ee and
91% yield (Table 4, entry 11 and 12). Simultaneously,
chiral catalyst 9g exhibited a similar level of stereose-
lectivity with an opposite sense of asymmetric induc-
tion and up to 92% ee can be obtained. This result in-
dicates that both the (R,R)- and the (S,S)-configura-
tion of 1,2-diaminocyclohexane matched the b-d-glu-
copyranose to enhance the stereochemical control
(Table 4, entry 13).
Figure 2. ORTEP presentation of the crystal structure of 8a,
with 20% probability displacement ellipsoids.
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Figure 3. Plausible reaction mechanism.
Figure 2, and the structure showed that the absolute Experimental Section
configuration of the DHPM main product was as-
signed as S.
Typical Procedure for the Preparation of 8
The possible mechanism for the reaction is shown
in Figure 3. In the transition state I (TS I), the thiour-
ea moiety of bifunctional catalyst 9f interacts through
hydrogen bonding with the acyl group of benzyli-
A solution of aldehyde 6 (0.75 mmol), urea/thiourea 5
(0.5 mmol), 2,4,6-trichlorobenzoic acid (0.0112 g, 0.05 mmol)
and t-BuNH2·TFA (0.009 g, 0.05 mmol) in CH2Cl2 (1 mL)
was stirred at room temperature for 1 h. Then the catalyst
9f (0.013 g, 0.025 mmol) and ethyl acetoacetate 7 (0.195 g,
1.5 mmol) were added sequentially. The reaction mixture
was stirred at room temperature for 3 days, and the crude
product was precipitated. The product was filtered by suc-
tion and washed twice with cold EtOAc to yield the DHPM
as a white solid.
ACHTUNGTRENNUNGdeneurea while the neighboring primary amine acti-
vates ethyl acetoacetate (7) involving an enamine in-
termediate. The obtained absolute configuration (S)
of DHPMs was explained by the transition state I, in
which the Si-face of the imine was predominantly ap-
proached by the enamine intermediate generated
from ethyl acetoacetate (7) and the primary amine
group of the bifunctional catalyst 9f. The attack of
the enamine to the Re-face of the benzylideneurea
was restricted by the cyclohexyl scaffold of the cata-
lyst. The mechanism indicates that the thiourea
Acknowledgements
We thank the Committee of Science and Technology of Tian-
moiety and cyclohexyl scaffold of the bifunctional cat- jin (07JCZDJC04800), the Research Foundation for the Doc-
toral Program of Higher Education of China (20070055042)
and Project 973 of the Ministry of Science and Technology of
China (2007CB914800) for financial support.
alyst play a significant role in controlling the regio-
and diastereoselectivity of the Biginelli reaction.
In conclusion, we have developed an enantioselec-
tive multicomponent Biginelli reaction catalyzed by a
chiral bifunctional primary amine-thiourea 9f and a
Brønsted acid as the combined catalyst with t-
BuNH2·TFA as additive. A wide range of optically
active dihydropyrimidines was obtained in high yields
with good to excellent enantioselectivities (up to 99%
ee). A plausible transition state has been proposed to
explain the origin of the activation and the asymmet-
ric induction. Further investigations on the diastereo-
selective Biginelli reaction and application of this
novel catalyst in other asymmetric reactions are cur-
rently underway in our laboratory.
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Adv. Synth. Catal. 2009, 351, 3057 – 3062