Primary amine catalyzed Biginelli reaction for the enantioselective synthesis of 3,4-dihydropyrimidin-2(1H)-ones

Article abstract of DOI:10.1002/ejoc.201000448

Several chiral primary amines, mainly those derived from cinchona alkaloids, were evaluated as organocatalysts for the asymmetric Biginelli reaction. With quinine-derived amine catalyst 1 and after extensive optimization of the reaction conditions, 3,4-di

Full text of DOI:10.1002/ejoc.201000448

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201000448
Primary Amine Catalyzed Biginelli Reaction for the Enantioselective Synthesis
of 3,4-Dihydropyrimidin-2(1H)-ones
Derong Ding[a] and Cong-Gui Zhao*[a]
Keywords: Organocatalysis / Enantioselectivity / Nitrogen heterocycles / Multicomponent reactions
Several chiral primary amines, mainly those derived from
cinchona alkaloids, were evaluated as organocatalysts for the
asymmetric Biginelli reaction. With quinine-derived amine
catalyst 1 and after extensive optimization of the reaction
conditions, 3,4-dihydropyrimidin-2(1H)-ones were obtained
in moderate to good yields and 51–78%ee from a three-com-
ponent reaction of aryl and aliphatic aldehydes, urea, and
acetoacetate.
current work. Herein we wish to disclose our study on the
use of primary amines, mainly those derived from cinchona
alkaloids, as catalysts in the asymmetric synthesis of
DHPMs using the Biginelli reaction.
Introduction
3,4-Dihydropyrimidin-2(1H)-one derivatives (DHPMs)
are very important pharmacologically active molecules and
have found applications as calcium channel modulators, α1a
adrenoceptor-selective antagonists, and inhibitors of the ki-
nesin motor protein and HIV.[1] The Biginelli reaction,[2]
which is a three-component reaction of an aromatic alde-
hyde, urea, and acetoacetate, is the most efficient method
for the assembly of these biologically significant heterocy-
clic compounds. Because it has been found that individual
enantiomers of a given DHPM may exhibit totally different
or even opposite pharmaceutical activities,[3] there has been
a lot of interest in developing highly enantioselective syn-
theses of DHPM derivatives in recent years.[4] For example,
Zhu and co-workers reported the first highly enantioselec-
tive synthesis of DHPMs by using a chiral ytterbium Lewis
acid catalyst in 2005.[5b] Soon afterwards, Gong and co-
workers successfully developed an asymmetric synthesis of
these compounds with excellent enantiocontrol by using
Results and Discussion
According to previous reports by Feng,[5e] Juaristi,[5f]
Wang,[5g] and Lee,[5h] the observed stereoselectivities in the
asymmetric synthesis of DHPMs catalyzed by secondary
amine catalysts were explained by an enamine activation
mechanism.[5e–5h] Because primary amines, especially those
derived from cinchona alkaloids, are also highly efficient
catalysts for organic reactions involving enamine intermedi-
ates,[6] we reasoned that these compounds should also be
good catalysts for the asymmetric synthesis of DHPMs.
Thus, we screened some readily available chiral primary
amine catalysts (1–7, Figure 1) in the three-component re-
action of benzaldehyde (8a), urea (9), and ethyl acetoacetate
(10) for the asymmetric synthesis of DHPM derivative 11a.
The results of the screening are summarized in Table 1.
As shown by the results in Table 1, when quinine-derived
amine 1 was used as the catalyst and HCl as the acid cocat-
alyst (10 mol-% each), the reaction of benzaldehyde (8a),
urea (9), and ethyl acetoacetate (10) in THF led to desired
product 11a in 64% yield and 66%ee after 3 d at room
temperature (Table 1, Entry 1). The absolute configuration
of the major enantiomer was determined to be R by com-
paring the measured optical rotation with reported data.[5]
Demethylated catalyst 2 yielded this product in a similar
yield after a reaction time of 5 d at room temperature, and
the ee value obtained was slightly lower (Table 1, Entry 2).
Quinidine-derived amine 3, which is a pseudoenantiomer of
1, gave the opposite enantiomer as the major product in
57%ee (Table 1, Entry 3). When similarly demethylated cat-
alyst 4 was used, the reaction became very sluggish and the
ee value obtained was much lower (40%; Table 1, Entry 4).
a
BINOL-derived Brønsted acid.[5c,5d] Besides Lewis
acids[5a,5b] and Brønsted acids,[5c,5d] asymmetric induction
in this reaction may also be achieved by using secondary
amines as the catalyst and a suitable acid as the cocata-
lyst.[5e–5i] The reported catalysts are mainly proline deriva-
tives.[5e–5h] In contrast, although primary amines are also
known to participate as catalysts in reactions that involve
enamine intermediates,[6] to the best of our knowledge,
there is no report on the use of primary amines as catalysts
in the enantioselective synthesis of DHPMs, except for the
use of bifunctional primary amine thioureas reported re-
cently by Chen and co-workers[5i] during the progress of our
[a] Department of Chemistry, University of Texas at San Antonio,
Texas, 78249-0698, USA
Fax: +1-210-458-7428
E-mail: cong.zhao@utsa.edu
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000448.
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Eur. J. Org. Chem. 2010, 3802–3805

Enantioselective Synthesis of 3,4-Dihydropyrimidin-2(1H)-ones
Table 1. Screening of the catalysts and optimization of the reaction
conditions.[a]
Entry Catalyst
Acid
Solvent
Time
[d]
Yield
[%][b]
ee
[%][c]
1
2
3
4
5
6
7
8
1
2
HCl
HCl
HCl
HCl
HCl
HCl
HCl
HCl
HCl
HCl
HCl
HCl
HCl
HCl
HCl
PhCO2H
2-NBA[g]
TFA
p-TSA
THF
THF
THF
THF
THF
THF
THF
dioxane
CHCl3
CH2Cl2
toluene
TFE[f]
CH3CN
DMSO
acetone
THF
5
5
5
8
9
5
6
7
5
5
9
5
5
5
5
15
15
5
8
6
7
5
5
5
6
6
64
63
51
21
trace
21
56
80
60
62
12
trace
85
83
43
Ͻ5
13
60
75
71
66
50
57[d]
40[d]
nd[e]
5
3
4
5
6
7
3
1
61
59
50
37
nd[e]
40
17
46
nd
0
44
55
20
52
61
62
64
73
72
9
1
10
11
12
13
14
15
16
17
18
19
20
21[h]
22[i]
23[i,j]
24[i,k]
25[i,k,l]
26[i,k,l]
1
1
1
1
Figure 1. Catalysts screened for the three-component synthesis of
DHPM 11a.
1
1
1
1
THF
THF
THF
These results indicate that both the reaction rate and the
enantioselectivity are highly sensitive towards subtle
changes in the structure of the catalyst. Although these cat-
alysts generate only mediocre ee values of the product, 1,2-
cyclohexanediamine (5) and its thiourea derivative 6 and
sulfonamide derivative 7 proved to be even poorer catalysts
for this reaction, because low yields and/or poor ee values
of the product were obtained (Table 1, Entries 5–7).
1
1
1
CF3SO3H THF
1
HCl
HCl
HCl
HCl
HCl
HCl
THF
THF
THF
THF
THF
THF
51
73
91
97
81
76
1
1
1
1[m]
1[n,o]
This screening identified quinine-derived amine 1 as the [a] Unless otherwise noted, all reactions were conducted with 8a
(0.25 mmol), 9 (0.25 mmol), and 10 (0.25 mmol) in the presence of the
best catalyst for this reaction. Then, we studied the solvent
effects on this reaction by using 1 as the catalyst. As re-
vealed in Table 1, a slightly lower ee value of 61% was ob-
catalyst (0.025 mmol, 10 mol-%) and the acid cocatalyst (0.025 mmol,
10 mol-%) in the specified solvent (1.5 mL) at room temperature.
[b] Yield of the isolated product after column chromatography.
tained with 1,4-dioxane (Table 1, Entry 8). When chloro-
form and dichloromethane were used as solvents, the ee val-
ues obtained were also inferior (59 and 50%, respectively;
Table 1, Entries 9 and 10). The reaction is also slower in
these three solvents (Table 1, Entries 8–10). Other common
organic solvents, such as toluene (Table 1, Entry 11), 2,2,2-
trifluoroethanol (Table 1, Entry 12), CH3CN (Table 1, En-
try 13), DMSO (Table 1, Entry 14), and acetone (Entry 15),
all led to poorer ee values of the product. Next, different
acid cocatalysts were evaluated. Weak acids such as benzoic
acid (Table 1, Entry 16) and 2-nitrobenzoic acid (Table 1,
Entry 17) are not effective in promoting the reactivity and
[c] Determined by the HPLC analysis on
a
Chiral-
Cel OD-H column. [d] The S enantiomer was obtained as the major
product. [e] Not determined. [f] 2,2,2-Trifluoroethanol. [g] 2-Nitroben-
zoic acid. [h] Conducted with 5 mol-% of the catalyst and 5 mol-% of
the acid cocatalyst. [i] Conducted with 20 mol-% of the catalyst and
20 mol-% of the acid cocatalyst. [j] Conducted with 8a (0.25 mmol),
9
(0.375 mmol), and 10 (0.75 mmol). [k] Conducted with 8a
(0.25 mmol), 9 (0.50 mmol), and 10 (1.25 mmol). [l] The reaction tem-
perature was 0 °C. [m] Catalyst 1 was recovered in 93% yield after the
reaction. [n] Carried out with recovered catalyst 1. [o] Catalyst 1 was
recovered in 98% yield after the reaction.
the enantioselectivity of this reaction at all. In contrast, ping the catalyst loading to 5 mol-% led to a lower yield
good yields of the product were obtained with a stronger and ee value of the product (Table 1, Entry 21). On the
acid, such as TFA (Table 1, Entry 18), p-toluenesulfonic other hand, increasing the catalyst loading to 20 mol-%
acid (Table 1, Entry 19), and trifluoromethanesulfonic acid only resulted in a slightly better product yield (Table 1, En-
(Table 1, Entry 20), albeit the ee values obtained were try 22). Nevertheless, we found that a much better product
slightly lower with these acid cocatalysts. Thus, THF was yield could be achieved if an excess amount of urea and
identified as the best solvent and HCl was identified as the acetoacetate was used together with a 20 mol-% loading of
best acid cocatalyst for this reaction. To obtain better yields the catalyst. For example, the yield improved to 91% when
and enantioselectivities in this reaction, the catalyst loading the molar ratio of 8a/9/10 was changed to 1:1.5:3 (Table 1,
and ratio of the three substrates were further studied. Drop- Entry 23). The yield was further improved to 97% if this
Eur. J. Org. Chem. 2010, 3802–3805
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D. Ding, C.-G. Zhao
SHORT COMMUNICATION
ratio was 1:2:5 (Table 1, Entry 24). Moreover, the ee values Table 2. Three-component reaction of aldehydes, urea, and acetoacet-
ate for the asymmetric synthesis of DHPMs.[a]
obtained for the product remained almost steady in these
two cases. Finally, the temperature effects were studied, and
it was found that lowering the reaction temperature to 0 °C
can improve the ee value to 73% (Table 1, Entry 25). Fur-
ther dropping the reaction temperature is impractical, as
the reaction becomes very sluggish. Although 10 mol-% of
catalyst 1 has to be used to achieve a good yield of the
product, it is possible to recover the catalyst in high yields
(93 to 98% yield; Table 1, Entries 25 and 26) during the
chromatographic purification of the product. Furthermore,
the recycled catalyst shows almost the same reactivity and
selectivity as the original catalyst (Table 1, Entry 26).
The scope of this reaction was then evaluated by using
compound 1 as the catalyst and HCl as the cocatalyst under
the optimized conditions (Table 1, Entry 25). The results
are collected in Table 2. Besides benzaldehyde (Table 2, En-
try 1), substituted benzaldehydes may also be applied as the
substrates in this reaction. The electronic nature of the sub-
stituent on the benzene ring was found to have influences
on both the reactivity and the enantioselectivity of this re-
action. Electron-donating groups, such as methyl or meth-
oxy groups, diminish slightly the reaction yield and the ee
Entry
R
Product
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
Ph
11a
11b
11c
11d
11e
11f
11g
11h
11i
81
53
71
53
61
63
68
20
14
21
43
73
69
4-MeC6H4
4-MeOC6H4
2-MeC6H4
4-FC6H4
4-ClC6H4
4-BrC6H4
4-NCC6H4
4-O2NC6H4
3-O2NC6H4
n-C6H13
51
53[d]
73
76
78
76
72
74
72
9
10
11
11j
11k
[a] All reactions were conducted with 8 (0.25 mmol), 9 (0.5 mmol),
and 10 (1.25 mmol) in the presence of catalyst 1 (0.05 mmol, 20 mol-
%) and HCl (0.05 mmol, 20 mol-%) in THF (1.5 mL) at 0 °C for 6 d.
[b] Yield of the isolated product after column chromatography. [c] Un-
less otherwise noted, ee values were determined by HPLC analysis on
values of this reaction as compared to the unsubstituted a ChiralCel OD-H column. [d] Determined by the HPLC analysis on
a ChiralPak AD-H column.
phenyl group (Table 2, Entries 2–4 vs. Entry 1). In contrast,
electron-withdrawing groups on the phenyl ring have no in-
fluence on the enantioselectivities (Table 2, Entries 5–10).
For example, similar ee values of 72 and 74% were obtained
for the strongly electron-withdrawing para- and meta-nitro-
substituted benzaldehydes, respectively (Table 2, Entries 9
imine gives an intermediate, which, after hydrolysis, intra-
molecular cyclization, and dehydration reaction, yields ob-
served R-configured product 11a.
and 10 vs. Entry 1). Nonetheless, whereas weak electron-
withdrawing groups only reduce the reaction yields slightly
(Table 2, Entries 5–7), strong electron-withdrawing groups,
such as cyano and nitro groups, diminish the yield dramati-
cally (Table 2, Entries 8–10). Although aromatic aldehydes
are often studied in the asymmetric synthesis of DHPMs,[5]
aliphatic aldehydes are seldom used as substrates.[5b,5c] To
the best of our knowledge, aliphatic aldehydes have never
been studied in an enamine-mediated asymmetric Biginelli
reaction. To test the scope our catalyst, we studied heptanal
in our reaction, and found the reaction gave comparable
enantioselectivity of the product (72%ee) as aromatic sub-
strate, although the yield of the product is much lower
(43%; Table 2, Entry 11).
On the basis of the mechanism proposed for the second-
ary-amine-catalyzed synthesis of DHPMs,[5e–5h] we believe
the present reaction also works through a dual activation
mechanism realized by quinine amine catalyst 1. The for-
mation of the R-configured product may be interpreted by
the proposed transition state in Scheme 1. As shown in
Scheme 1, the imine formed between benzaldehyde and
urea is hydrogen bonded to the protonated quinuclidine
Scheme 1. Plausible transition state for the formation of the R-
configured enantiomer (QNH2 = catalyst 1).
Conclusions
We have demonstrated that chiral primary amines, such
backbone of catalyst 1. Such a hydrogen bond not only acti- as the amine derived from quinine, may be used as catalysts
vates the imine for nucleophilic attack, but also helps bring for the three-component reaction of aldehydes, urea, and
the imine closer to the reaction center and limits its possible acetoacetate in the enantioselective synthesis of 3,4-dihy-
orientations. The primary amine group on the side chain of dropyrimidin-2(1H)-ones (DHPMs). Under the optimized
the catalyst activates acetoacetate through the formation of conditions, the corresponding DHPMs may be obtained in
an enamine. Attack of this enamine onto the Si face of the moderate to good yields and good ee values (up to 78%ee).
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Enantioselective Synthesis of 3,4-Dihydropyrimidin-2(1H)-ones
[2]
[3]
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Experimental Section
General: 1H NMR spectra were obtained with a Varian INOVA
500 MHz or a GE 300 MHz spectrometers by using residual sol-
vent as the standard. TLC was performed with silica gel GF254
precoated on aluminum plates, and spots were visualized with UV
and/or iodine vapor. Flash column chromatography was performed
on silica gel. HPLC analysis was performed with a Shimadzu in-
strument with LC-20AT pump and SPD-20AV UV/Vis detector.
ChiralCel and ChiralPak HPLC columns were purchased from
Daicel Chemical Industry, Ltd. Compounds used in this study were
purchased from Aldrich, Alfa-Aesar, Acros, TCI, or Strem and
were used as received. Toluene, CH2Cl2, CHCl3, and CH3CN were
distilled from CaH2. THF was freshly distilled from benzophenone
and sodium metal. DMSO was dried with molecular sieves. Cata-
lysts 1,[8] 2,[9] 3,[8] 4,[9] 6,[10] and 7[11] were synthesized according to
reported procedures. Unless otherwise specified, all reactions were
carried out at ambient temperature in oven-dried glassware.
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General Procedure for the Three-Component Reaction of Aldehyde,
Urea, and Acetoacetate: To a mixture of the aldehyde (0.25 mmol)
and urea (30.0 mg, 0.5 mmol) in THF (1.5 mL) at 0 °C was added
ethyl acetoacetate (162.7 mg, 1.25 mmol), catalyst 1 (16.2 mg,
0.05 mmol), and HCl (4.0  in dioxane, 13 µL, 0.05 mmol). The
mixture was further stirred for 6 d at this temperature. Then the
reaction mixture was directly transferred to a silica gel column and
purified by column chromatography (hexane/ethyl acetate, 1:1) to
afford the DHPM products. All the products are known com-
pounds and have identical spectroscopic data as those report-
ed.[5b,5c]
[6]
Catalyst Recovering: Once the DHMP product was separated, the
column was flushed with Et3N/CH3OH/EtOAc (1:2:4) as the eluent
to isolate catalyst 1 (as its HCl salt, Rf = 0.62). The fractions were
combined and the solvents were removed under reduced pressure.
The residue was dissolved in CH2Cl2 (10 mL), washed with aque-
ous NaHCO3 (5 mL), and dried with Na2SO4. The solvent was
removed to afford the catalyst (15.0 mg, 93% recovery).
(R)-5-Ethoxycarbonyl-4-(n-hexyl)-6-methyl-3,4-dihydropyrimidin-
2(1H)-one (11k):[7,12] Yield: 28.8 mg, 43%, white solid, m.p. 126–
128 °C. [α]2D3 = +40.0 (c = 1.02, MeOH). 1H NMR (500 MHz,
CDCl3): δ = 8.04 (br. s, 1 H), 5.75 (br. s, 1 H), 4.29–4.32 (m, 1 H),
4.14–4.24 (m, 2 H), 2.29 (s, 3 H), 1.49–1.60 (m, 2 H), 1.23–1.43 (m,
1 H), 0.87–0.92 (m, 3 H) ppm.
Supporting Information (see footnote on the first page of this arti-
cle): 1H NMR spectroscopic data and spectra of the products;
HPLC conditions and chromatograms.
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Acknowledgments
Generous financial support of this research from the National In-
stitutes of Health, National Institute of General Medical Sciences
(Grant no. SC1GM082718) and the Welch Foundation (Grant No.
AX-1593) is gratefully appreciated.
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Received: April 4, 2010
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Published Online: June 8, 2010
Eur. J. Org. Chem. 2010, 3802–3805
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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