Enantioselective Synthesis of 3,4-Dihydropyrimidin-2(1 H)-ones through Organocatalytic Transfer Hydrogenation of 2-Hydroxypyrimidines

Article abstract of DOI:10.1021/acs.joc.8b03128

Chiral phosphoric acid-catalyzed transfer hydrogenation of 2-hydroxypyrimidines has been successfully realized using Hantzsch ester or dihydrophenanthridine as the hydrogen source, furnishing the chiral 3,4-dihydropyrimidin-2(1H)-ones (DHPMs) with excelle

Full text of DOI:10.1021/acs.joc.8b03128

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Enantioselective Synthesis of 3,4-Dihydropyrimidin -2(1H)-ones through
Organocatalytic Transfer Hydrogenation of 2-Hydroxypyrimidines
Fan-Jie Meng, Lei Shi, Guang-Shou Feng, Lei Sun, and Yong-Gui Zhou
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b03128 • Publication Date (Web): 13 Mar 2019
Downloaded from http://pubs.acs.org on March 14, 2019
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Enantioselective Synthesis of 3,4-Dihydropyrimidin-2(1H)-ones
through Organocatalytic Transfer Hydrogenation of 2-
Hydroxypyrimidines
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Fan-Jie Meng,a,b Lei Shi,a,b* Guang-Shou Feng,a Lei Suna and Yong-Gui Zhoua*
aState Key Laboratory of Catalysis, Dalian Institute of Chemical Physics, Chinese
Academy of Sciences, Dalian 116023, P. R. China.
bState Key Laboratory of Fine Chemicals, School of Chemistry, Dalian University of
Technology, Dalian 116024, P. R. China.
*E-mail: shileichem@dlut.edu.cn
*E-mail:ygzhou@dicp.ac.cn
ABSTRACT
Chiral phosphoric acid-catalyzed transfer hydrogenation of 2-hydroxypyrimindines has been successfully
realized using Hantzsch ester or dihydrophenanthridine as hydrogen sources, furnishing the chiral 3,4-
dihydropyrimidin-2(1H)-ones (DHPMs) with excellent yields and up to 99% ee of enantioselectivities.
Notably, a novel kind of chiral DHPMs with an alkyl stereogenic center can be prepared through highly
chemoselective transfer hydrogenation.
Functionalized 3,4-dihydropyrimidin-2(1H)-ones (DHPMs), the products of the well-known Biginelli three-
component condensation reaction,1 posses a wide range of pharmacological properties, including anticancer
activity, calcium channel inhibition, anti-inflammatory activity, antibacterial activity, etc.2 Intensive
researches suggested that both enantioisomers of DHPMs often show very different or even opposite biological
activies. For example, (S)-enantiomer of Monastrol is a more potent inhibitor of Eg5 ATPase activity than the
(R)-enantiomer3 and the (R)-SQ 32926 presents >400 fold more antihypertensive activity as a calcium channel
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blocker than its (S)-enantiomer4 (Figure 1). Therefore, highly enantioselective synthesis of optically pure
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DHPMs is undoubtedly a desirable objective.
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Figure 1. Chiral DHPMs with pharmacological activities.
Conceptually, asymmetric catalytic Biginelli reaction is the most straightforward approach to chiral
DHPMs.5 However, the preparation of this kind of important compound always relied on the resolution of
racemic mixture4, and chiral auxiliary-assisted synthesis7 until a breakthrough has been made on the
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asymmetric catalytic Biginelli reaction. In 2005, a new chiral ytterbium complex was designed and synthesized
in Zhu’s lab, which is able to catalyze asymmetric Biginelli reaction with unprecedented enantioselectivity
(80-99% ee).8 Shortly afterwards, Gong and coworkers reported the first organocatalytic enantioselective
Biginelli reaction using a BINOL-derived chiral phosphoric acid as catalyst, giving structurally diverse
DHPMs with high ees.9 Feng described an enantioselective Biginelli reaction catalyzed by a chiral simple
secondary amine combined with achiral Brønsted acid in a dual activation mode.10 Since then, a variety of
catalysts has been successfully developed to promote this useful transformation, such as chiral Brønsted
acids,11 proline derivatives,12 prime amines13 and etc. Despite achievements obtained in asymmetric Biginelli
reaction, new approaches to chiral DHPMs is still of great value. In facts, asymmetric hydrogenation of
aromatic compounds has been proved highly effective for preparing chiral cyclic molecules.14 Partial reduction
of pyrimidin-2-one may also directly construct the Beginelli-type DHPMs based on retrosynthetic analysis.
Scheme 1. Enantioselective Catalytic Synthesis of Chiral 3,4-dihydropyrimidin-2-ones.
Very recently, our group realized an asymmetric hydrogenation of 2-hydroxypyrimindines using chiral Pd
or Ir catalyst to offer chiral cyclic ureas or DHPMs with high ees, which presents a new facile method to
synthesize this kind of important compounds.15a, 15b Herein, we disclosed the first asymmetric biomimetic
transfer hydrogenation of pyrimindines catalyzed by chiral phosphoric acid with Hantzsch ester or
dihydrophenanthridine (DHPD) as a hydride donor, furnishing chiral DHPMs with excellent enantioselectivity
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and chemoselectivity.
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Table 1.The Evaluation of Reaction Parametersa
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Entry
1
Solvent
THF
Yield b(%)
Eec(%)
40
CPA
3a
3a
3a
3a
3a
3a
3a
3a
3b
3c
HEH (R)
4a (Et)
4a (Et)
4a (Et)
4a (Et)
4a (Et)
4a (Et)
4b (Me)
4c (tBu)
4a (Et)
4a (Et)
4a (Et)
4a (Et)
4a (Et)
97
94
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94
63
88
97
66
78
99
2
CH2Cl2
EtOAc
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3
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4
1,4-dioxane
Toluene
Benzene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
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5
69
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66
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65
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69
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74
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70
91
3d
3e
92
94
3f
[a] Reaction condition: 1a (0.1 mmol), CPA-3 (5.0 mol%), HEH (1.2 eq.), solvent
(2.0 mL), 24 h, 40 oC. [b] Isolated yields. [c] Determined by chiral HPLC analysis.
With ethyl 2-hydroxy-4,6-diphenylpyrimidine-5-carboxy-late (1a) as the model substrate, we began the
pursuit of the enantioselective transfer hydrogenation for synthesis of chiral DHPMs. Initially, solvent effects
were evaluated with one representative set of reaction conditions exemplified in Table 1 (entries 1-6). In most
solvent, this transformation could smoothly occur in presence of CPA 3a and Hantzsch ester 4a, giving the
desired chiral DHPMs 2a with good isolated yield. But toluene gave the best in term of both yield and
enantioselectivity (entry 5). When the HEH 4c with bulky t-butyl group used as hydride donor, the yield
dramatically dropped down to only 63% (entry 8). Next, different CPAs were screened with 4a in toluene
(entries 9-13). The results showed that the catalysts bearing bulky substituent at C3 position exhibit more
prominent enantioselectivities. To our delight, CPA 3f was selected as the best one for 99% yield and 94% ee
obtained (entry 13).
Scheme 2. Substrate Scope
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Reaction condition: 1 (0.2 mmol), CPA-3f (5.0 mol%), HEH 4a (1.2 eq.), toluene (4.0 mL), 24 h, 40 oC
Having defined an optimal reaction protocol, exploration of substrate scope was carried out to test the
generality (Scheme 2). In general, a variety of 2-hydroxy-4,6-diarylpyrimidine-5-carboxylate derivatives 1
were converted into chiral DHPMs 2 with good enantioselectivities and yields. It appears that both yield and
enantioselectivity are very sensitive for the position of substitutes on the phenyl ring. The substrates with para-
substituented phenyl group (2b) underwent the reaction to afford the reduced product with moderate
enantioselectivities (83% ee). When bearing meta-substituented phenyl group (2c, 2d, 2e, 2f), DHPMs were
furnished with much higher enantioselectivities (up to 97% ee) than the substrates bearing 4-substituent phenyl.
And an ortho-substituent group at phenyl ring would suppress this reduction process completely due to a steric
hindrance. Replacement of the ethyl ester with methyl (2g, 2h, 2i), tert-butyl ester (2j) or amide (2k) in the
parent substrate kept a high level of enantioselectivities (92~> 99% ee) and yields. Ethyl 2-hydroxy-4,6-
dimethyl pyrimidine-5-carboxylate also was tested and only a low ee obtained, albeit 97% yield (2l).
Next, we turned our attention to multisubstituted 2-hydroxypyrimidines 5 with an unsymmetrical structure,
which may lead to the more classic Biginelli products. In the initial investigation, an inseparable mixture of
6a and 7a was obtained under the standard reaction condition. After careful reoptimization of condition,
excellent chemoselectivity can be achieved with DHPD used as alternative hydride donor.16 This improvement
of chemoselectivity is possibly attributed to the discrepancy of hydride-transfer ability of hantzsch ester and
dihydrophenanthridine. With weaker hydride donor than hantzsch ester, DHPD could be a proper reductant in
accessing selective hydrogenation of molecules containing more than one unsaturated bond. 16b It is interesting
that compound 6a was detected exclusively in the crude reaction mixture in moderate enantioselectivity (77%
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ee). To the best of our knowledge, effective synthesis of DHPMs with an alkyl substituted chiral center is still
rare. Some novel chiral DHPMs with methyl substituted chiral carbon atom at C-4 position were prepared with
good yields and moderate values of ee (Scheme 3). Unfortunately, this kind of reduction failed to undergo in
further study on scope of other alkyl substituted substrates.
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Scheme 3. Enantioselective Transfer Hydrogenation of Unsymmetrical Multisubstituted 2-Hydroxy-
pyrimidines
Reaction condition: 5 (0.2 mmol), CPA-3f (5.0 mol %), DHPD (1.2 eq.), benzene (4.0 mL),
48 h, 40 oC. DHPD: dihydrophenanthridine.
To demonstrate the practical utility of this method, chiral DHPM 2a was prepared on a gram scale with 98%
yield and 94% ee under the optimal conditions. After recrystallization once, the ee was rised up to >99%.
Treating 2a with Lawesson's reagent gave the corresponding 3,4-dihydro-pyrimidin-2(1H)-thione 8 in nearly
quantitative yield without any loss of value of ee (Scheme 4). This procedure provides new accesses to a wide
spectrum of structurally diverse dihydropyrimidinethiones and their pharmaceutically relevant derivatives
with high enantiomeric purity.9
Scheme 4. Gram Scale Experiment and Synthesis of Chiral 3,4-dihydropyrimidin-2(1H)-thione
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Based on the above experimental results and the relative researches14h, a plausible stepwise hydrogenation
process was proposed (Scheme 5). Firstly, the chiral phosphoric acid facilitated the reversible isomerization
to form the active tautomer 9. Secondly, C=N double bond of 9 is hydrogenated to give the final chiral product.
The origin of enantioselectivity can be explained by the stereochemical model as illustrated in Scheme 5.
These two hydrogen bonding interaction and the effect of steric hindrance build up “three-point contact model”
via re-face attach that determines the stereoselectivity.
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Scheme 5. Proposed Reaction Pathway and Transition State
In conclusion, we reported the first asymmetric biomimetic transfer hydrogenation of pyrimindines
catalyzed by chiral phosphoric acid, successfully furnishing a chiral DHPMs with excellent yields and
enantioselectivities (up to 99% ee). In partically, a novel chiral DHPMs with an alkyl stereogenic center can
be prepared through highly chemoselective tranfer hydrogenation, which is seldom descrided before. The
detailed investigation on potential bioactivity of this new kind of chiral DHPMs is ongoing in our cooperative
lab.
EXPERIMENTAL SECTION
Commercially available reagents were used without further purification. Solvents were treated prior to use
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according to the standard methods. H NMR, 13C{1H} NMR and 19F NMR spectra were recorded at room
temperature in CDCl3on 400 MHz instrument with tetramethylsilane (TMS) as internal standard. Enantiomeric
excess was determined by HPLC analysis, using chiral column described below in detail. Optical rotations
were measured by polarimeter. Flash column chromatography was performed on silica gel (200-300 mesh).
General Procedure for Trisubstituted 2-Hydroxypyrimidines: Trisubstituted 2-hydroxypyrimidine
derivatives 1 can be conveniently prepared according to the known literature procedure with some minor
modifications.1 Among them, the compounds 1a,15a 1d,15a 1e,15a 1j,15a 5a-5b,17a 5c,17b 5d-5f,17c are known (see
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Scheme S1).
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Copper(II) trifluoromethanesulfonate (0.271 g, 5.0 mol %) was added into a solution of aldehyde (15.0
mmol), urea (1.08 g, 18.0 mmol), and ethyl 3-oxo-3-arylpropanoate (15.0 mmol) in 40 mL ethanol. After
heated at 80 oC under nitrogen for 24 h in oil bath, the reaction mixture was cooled to 0 oC, the precipitation
was collected by filtration and dried. The resulting white powder was triturated with cooled ethanol to afford
S-1 or S-5 as a pale yellow powder.
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A solution of above S-1 or S-5 (3.0 mmol), CuCl2•2H2O (5.0 mg, 1.0 mol %), potassium carbonate (41 mg,
10 mol %) in dichloromethane (6.0 mL) was heated at 40 oC for 30 min in oil bath, and then 65 wt% tert-butyl
hydroperoxide (0.832 g, 6.0 mmol) was added dropwise over a period of 10 minutes. The resulting mixture
was stirred at 35 °C for 24 h in oil bath. The saturated aqueous sodium thiosulfate (10 mL) was added to
quench the excess tert-butyl hydroperoxide. After stirred for 20 minutes, the mixture was extracted with
dichloromethane (40 mL×3). The combined organic layer was dried over anhydrous sodium sulfate,
concentrated in vacuo. The crude product was purified by flash column chromatography using the hexanes
and ethyl acetate as eluent to give the desired products.
Ethyl 4,6-bis(4-chlorophenyl)-2-hydroxypyrimidine-5-carboxylate (1b): 0.553 g, 36% yield (2 steps), new
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compound, white solid, mp: 95-96 C, Rf = 0.45(dichloromethane/methanol = 10/1); H NMR (400 MHz,
CDCl3) δ (ppm) 13.43 (s, 1H), 7.57 (d, J = 8.6 Hz, 4H), 7.45 (d, J = 8.6 Hz, 4H), 3.95 (q, J = 7.1 Hz, 2H), 0.91
(t, J = 7.1 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ (ppm) 165.9, 157.9, 137.8, 129.6, 129.1, 111.9, 62.1,
13.4. HRMS (ESI) m/z Calculated for C19H15Cl2N2O3 [M+H]+ 389.0454, found 389.0459.
Ethyl 4,6-bis(3-chlorophenyl)-2-hydroxypyrimidine-5-carboxylate (1c): 2.942 g, 52% yield (2 steps), new
compound, white solid, mp: 160-161 oC, Rf = 0.30 (hexanes/ethyl acetate = 1/1); 1H NMR (400 MHz, CDCl3)
δ (ppm) 7.61 (s, 2H), 7.58-7.48 (m, 4H), 7.44-7.42 (m, 2H), 4.01 (q, J = 7.1 Hz, 2H), 0.97 (t, J = 7.1 Hz, 3H).
13C{1H} NMR (100 MHz, CDCl3) δ (ppm) 165.5, 157.6, 135.6, 134.8, 131.4, 130.2, 128.3, 126.3, 112.2, 62.2,
13.5. HRMS (ESI) m/z Calculated for C19H15Cl2N2O3 [M+H]+ 389.0454, found 389.0452.
Ethyl 4,6-bis(3-fluorophenyl)-2-hydroxypyrimidine-5-carboxylate (1d): 2.549 g, 52% yield (2 steps), new
compound, white solid, mp: 184-185 oC, Rf = 0.30 (hexanes/ethyl acetate = 1/1); 1H NMR (400 MHz, CDCl3)
δ (ppm) 7.37-7.22(m, 8H), 3.99 (q, J = 7.1 Hz, 2H), 0.93 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3)
δ (ppm) δ 165.6, 162.5 (d, JC-F = 248.4 Hz), 157.7, 136.0, 130.6 (d, JC-F = 8.1 Hz), 123.9 (d, JC-F = 3.1
Hz), 118.4 (d, JC-F = 21.1 Hz), 115.5, 115.3, 112.1, 62.1, 13.4. 19F NMR (376 MHz, CDCl3) δ (ppm) -111.16.
HRMS Calculated for C19H15F2N2O3 [M+H]+ 357.1045, found 357.1049.
Ethyl 2-hydroxy-4,6-di-m-tolylpyrimidine-5-carboxylate (1e): 1.104 g, 55% yield (2 steps), new compound,
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white solid, mp: 190-191 C, Rf = 0.51 (dichloromethane/methanol = 20/1); H NMR (400 MHz, CDCl3) δ
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(ppm) 13.04 (s, 1H), 7.42-7.29 (m, 8H), 3.93 (q, J = 6.7 Hz, 2H), 2.38 (s, 6H), 0.88 (t, J = 6.9 Hz, 3H). 13C{1H}
NMR (100 MHz, CDCl3) δ (ppm) 165.9, 157.2, 137.9, 131.4, 128.2, 128.1, 124.6, 111.4, 61.2, 20.9, 12.9.
HRMS (ESI) m/z Calculated for C21H21N2O3 [M+H]+ 349.1547, found 349.1553.
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Methyl 2-hydroxy-4,6-diphenylpyrimidine-5-carboxylate (1g): 0.969 g, 57% yield (2 steps), new compound,
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white solid, mp: 215-216 C, Rf = 0.35 (dichloromethane/methanol = 20/1); H NMR (400 MHz, CDCl3) δ
(ppm) 13.14 (s, 1H), 7.63-7.61 (m, 4H), 7.52-7.48 (m, 6H), 3.46 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ
(ppm) 166.9, 157.9, 131.3, 128.8, 128.7, 128.1, 128.0, 111.6, 52.5. HRMS (ESI) m/z Calculated for
C18H15N2O3 [M+H]+ 307.1077, found 307.1075.
Methyl 2-hydroxy-4,6-bis(3-methoxyphenyl)pyrimidine-5-carboxylate (1h): 2.356 g, 42% yield (2 steps),
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new compound, white solid, mp: 168-169 C, Rf = 0.30 (hexanes/ethyl acetate = 1/1); H NMR (400 MHz,
CDCl3) δ (ppm) 7.39-7.35 (m, 2H), 7.19-7.16 (m, 4H), 7.07-7.04 (m, 2H), 3.86 (s, 6H), 3.50 (s, 3H). 13C{1H}
NMR (100 MHz, CDCl3) δ (ppm) 166.9, 159.7, 157.7, 135.3, 129.9, 120.2, 117.7, 113.0, 111.7, 55.5, 52.6.
HRMS (ESI) m/z Calculated for C20H19N2O5 [M+H]+ 367.1288, found 367.1290.
Methyl 2-hydroxy-4,6-di-m-tolylpyrimidine-5-carboxylate (1i): 2.195 g, 40% yield (2 steps), new compound,
white solid, mp: 252-253 oC, Rf = 0.30 (hexanes/ethyl acetate = 1/1); H NMR (400 MHz, DMSO) δ (ppm)
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12.53 (s, 1H), 7.39-7.30 (m, 8H), 3.39 (s, 3H), 2.37 (s, 6H). 13C{1H} NMR (100 MHz, DMSO) δ (ppm) 167.6,
138.3, 131.7, 128.9, 128.8, 125.3, 100.0, 52.7, 21.4. HRMS (ESI) m/z Calculated for C20H19N2O3 [M+H]+
335.1390, found 335.1392.
tert-Butyl 2-hydroxy-4,6-diphenylpyrimidine-5-carboxylate (1j): 1.697 g, 67% yield (2 steps), new
compound, white solid, mp: 209-210 oC, Rf = 0.45 (ethyl acetate); 1H NMR (400 MHz, CDCl3) δ (ppm) 7.65-
7.63 (m, 4H), 7.52-7.47 (m, 6H), 1.15 (s, 9H). 13C{1H} NMR (100 MHz, CDCl3) δ (ppm) 164.9, 157.7, 130.9,
128.6, 128.2, 83.0, 27.3. HRMS (ESI) m/z Calculated for C21H21N2O3 [M+H]+ 349.1547, found 349.1548.
N, N-diethyl-2-hydroxy-4,6-diphenylpyrimidine-5-carboxamide (1k): 1.358 g, 56% yield (2 steps), new
compound, white solid, mp: 225-226 oC, Rf = 0.25 (ethyl acetate); 1H NMR (400 MHz, CDCl3) δ (ppm) 7.80-
7.78 (m, 4H), 7.49-7.43 (m, 6H), 3.19-3.18 (m, 2H), 2.85-2.83 (m, 2H), 0.79 (t, J = 7.1 Hz, 3H), 0.49 (t, J =
7.1 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ (ppm) 164.9, 157.8, 130.7, 128.4, 128.1, 113.5, 42.4, 38.3,
12.4, 10.9. HRMS (ESI) m/z Calculated for C21H22N3O2 [M+H]+ 348.1707, found 348.1710.
GeneralProcedure for Hydrogenation of 2-Hydroxypyrimidines: A mixture of 2-hydroxypyrimidines1
(0.20 mmol), Hantzsch ester 4a (61 mg, 0.24 mmol, 1.2 equiv), and chiral phosphoric acid (R)-3f (7.5 mg,
o
0.01 mmol, 5 mol %) in toluene (4 mL) was stirred at 40 C under nitrogen for 24 h in oil bath. After the
reaction was completed (determined by TLC), the solvent was removed under the reduced pressure. The
residue was purified by flash chroma- tography on silica gel using the dichloromethane/methanol as eluent to
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give the desired product 2. The enantiomeric excesses were determined by chiral HPLC.
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Ethyl (R)-(+)-2-oxo-4,6-diphenyl-1,2,3,4-tetrahydropyrimidine-5-carboxylate (2a): 63 mg, 98% yield,
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known compound,15 white solid, Rf = 0.45 (dichloromethane/methanol = 20/1), 94% ee, [α]20 = +27.43 (c
D
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0.74, MeOH). [lit.15: []20D= -31.1 (c 0.44, MeOH) for 97% ee (S)], 1H NMR (400 MHz, CDCl3) δ (ppm) 7.43-
7.25 (m, 10H), 7.09 (s, 1H), 5.98 (s, 1H), 5.48 (s, 1H), 3.84-3.80 (m, 2H), 0.80 (t, J = 7.1 Hz, 3H). 13C{1H}
NMR (100 MHz, CDCl3) δ (ppm) 165.5, 153.7, 147.6, 143.7, 134.8, 129.4, 128.8, 128.3, 128.0, 127.9, 126.6,
102.0, 60.0, 55.3, 13.6. HPLC: Chiracel AD-H column, 254 nm, 30 oC, hexane/i-propanol = 80/20, flow = 0.7
mL/min, retention time 13.8 min(maj) and 17.3 min.
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Ethyl (R)-4,6-bis(4-chlorophenyl)-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (2b): 77 mg, 99%
yield, new compound, white solid, mp: 190-191oC, Rf = 0.45 (dichloromethane/methanol = 30/1), 83% ee,
[α]20D = +26.02 (c 0.88, MeOH). 1H NMR (400 MHz, CDCl3) δ (ppm) 7.90 (s, 1H), 7.36-7.24 (m, 8H), 6.50
(s, 1H), 5.37 (d, J = 3.0 Hz, 1H), 3.88 -3.83 (m, 2H), 0.87 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3)
δ (ppm) 164.9, 153.1, 146.2, 141.8, 135.8, 134.0, 133.1, 129.6, 129.1, 128.5, 127.9, 102.4, 60.3, 55.1, 13.6.
HPLC: Chiracel AD-H column, 254 nm, 30oC, hexane/i-propanol = 80/20, flow = 0.7 mL/min, retention time
13.2 min(maj) and 15.7 min. HRMS (ESI) m/z Calculated for C19H17Cl2N2O3 [M+H]+ 391.0611, found
391.0606.
Ethyl (R)-4,6-bis(3-chlorophenyl)-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (2c): 76 mg, 97%
yield, new compound, white solid, mp: 208-209 oC, Rf = 0.60 (hexanes/ethyl acetate = 1/1), 92% ee, [α]20
=
D
1
+8.15 (c 0.54, MeOH). H NMR (400 MHz, CDCl3) δ (ppm) 7.59 (s, 1H), 7.42-7.21 (m, 9H), 6.20 (s, 1H),
5.47 (s, 1H), 3.91-3.86 (m, 2H), 0.89 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ (ppm) 164.1,
152.1, 145.3, 144.6, 135.8, 134.2, 133.6, 129.7, 129.2, 129.1, 128.0, 127.9, 126.4, 125.7, 124.2, 102.0, 59.8,
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54.9, 13.0. HPLC: Chiracel AD-H column, 254 nm, 30 C, hexane/i-propanol = 80/20, flow = 0.7 mL/min,
retention time 14.3 min(maj) and 16.2 min. HRMS (ESI) m/z Calculated for C19H17Cl2N2O3 [M+H]+ 391.0611,
found 391.0615.
Ethyl (R)-4,6-bis(3-fluorophenyl)-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (2d): 70 mg, 97%
yield, new compound, white solid, mp: 184-185 oC, Rf = 0.60 (hexanes/ethyl acetate = 1/1), 91% ee, [α]20
=
D
-3.87 (c 0.80, MeOH). 1H NMR (400 MHz, CDCl3) δ (ppm) 8.19 (s, 1H), 7.35-7.02 (m, 8H), 6.79 (s, 1H), 5.40
(d, J = 3.2 Hz, 1H), 3.92-3.86 (m, 2H), 0.88 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ (ppm)
164.9, 163.0 (d, JC-F = 246.8 Hz), 162.2 (d, JC-F = 247.1 Hz), 153.3, 146.2 (d, JC-F = 2.0 Hz), 145.8 (d,
JC-F = 6.1 Hz), 136.5 (d, JC-F = 8.1 Hz), 130.4 (d, JC-F = 8.1 Hz), 129.8 (d, JC-F = 8.2 Hz), 124.0 (d, JC-F
= 3.0 Hz), 122.1 (d, JC-F = 2.8 Hz), 116.5 (d, JC-F = 21.0 Hz), 115.6 (d, JC-F = 22.9 Hz), 115.1 (d, JC-F
=
21.2 Hz), 113.5 (d, JC-F = 22.0 Hz), 102.2, 60.3, 54.9, 13.5. 19F NMR (376 MHz, CDCl3) δ (ppm) -112.01 ,
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-112.49. HPLC: Chiracel AD-H column, 254 nm, 30 C, hexane/i-propanol = 85/15, flow = 0.9 mL/min,
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retention time 13.3 min(maj) and 15.0 min. HRMS (ESI) m/z Calculated for C19H17F2N2O3 [M+H]+ 359.1202,
found 359.1204.
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compound, white solid, mp: 196-197 C, Rf = 0.35 (dichloromethane/methanol = 30/1), 94% ee, [α]20
=
D
+25.18 (c 0.81, MeOH). 1H NMR (400 MHz, CDCl3) δ (ppm) 7.42 (s, 1H), 7.24-7.09 (m, 8H), 6.27 (s, 1H),
5.39 (d, J = 2.7 Hz, 1H), 3.86-3.81 (m, 2H), 2.33 (d, J = 4.8 Hz, 6H), 0.83 (t, J = 7.1 Hz, 3H). 13C{1H} NMR
(100 MHz, CDCl3) δ (ppm) 165.4, 153.0, 147.1, 143.5, 138.4, 137.8, 135.0, 130.2, 128.8, 128.7, 128.6, 128.1,
o
127.4, 125.2, 123.7, 102.2, 59.9, 55.8, 21.6, 21.3, 13.6. HPLC: Chiracel AD-H column, 254 nm, 30 C,
hexane/i-propanol = 80/20, flow = 0.8 mL/min, retention time 10.1 min(maj) and 12.9 min. HRMS (ESI) m/z
Calculated for C21H23N2O3 [M+H]+ 351.1703, found 351.1700.
Ethyl (R)-4,6-bis(3-methoxyphenyl)-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (2f): 75 mg, 99%
yield, known compound,15 white solid, Rf = 0.45 (dichloromethane/methanol = 20/1), 97% ee, [α]20D = +23.78
(c 0.74, MeOH). [lit.15: [α]20D= -22.4 (c 0.58, MeOH) for 99% ee (S)], 1H NMR (400 MHz, CDCl3) δ (ppm)
7.69 (s, 1H), 7.27-7.22 (m, 2H), 6.99-6.98 (m, 2H), 6.96-6.80 (m, 4H), 6.50 (s, 1H), 5.37 (d, J = 2.4 Hz, 1H),
3.87-3.82 (m, 2H), 3.76 (d, J = 6.7 Hz, 6H), 0.85 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ (ppm)
165.3, 159.9, 159.3, 153.1, 147.0, 145.0, 136.1, 129.9, 129.2, 120.6, 118.8, 115.3, 113.5, 113.2, 112.5, 102.0,
60.0, 55.6, 55.3, 55.2, 13.6. HPLC: Chiracel AD-H column, 254 nm, 30 oC, hexane/i-propanol = 70/30, flow
= 0.8 mL/min, retention time 14.8 min(maj) and 16.4 min.
Methyl (R)-2-oxo-4,6-diphenyl-1,2,3,4-tetrahydropyrimidine-5-carboxylate (2g): 61 mg, 98% yield, new
o
compound, white solid, mp: 211-212 C, Rf = 0.45 (dichloromethane/methanol = 30/1), 92% ee, [α]20
=
D
+10.33 (c 1.22, MeOH). 1H NMR (400 MHz, CDCl3) δ (ppm) 7.44 -7.31 (m, 10H), 7.02 (brs, 1H), 5.90 (brs,
1H), 5.52 (s, 1H), 3.41 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ (ppm) 165.2, 152.6, 147.0, 142.9, 134.3,
o
129.1, 128.4, 127.7, 127.5, 126.1, 126.0, 101.4, 55.1, 50.6. HPLC: Chiracel IA column, 254 nm, 30 C,
hexane/i-propanol = 80/20, flow = 0.8 mL/min, retention time 11.1 min(maj) and 14.5 min. HRMS (ESI) m/z
Calculated for C18H17N2O3 [M+H]+ 309.1234, found 309.1237.
Methyl (R)-4,6-bis(3-methoxyphenyl)-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (2h): 72 mg, 97%
yield, new compound, white solid, mp: 209-210 oC, Rf = 0.60 (dichlorome- thane/methanol = 30/1), > 99% ee,
[α]20D = +26.61 (c 1.30, MeOH). 1H NMR (400 MHz, DMSO) δ (ppm) 9.28 (s, 1H), 7.86 (s, 1H), 7.30 (t, J =
7.8 Hz, 2H), 6.99-6.86 (m, 6H), 5.22 (d, J = 3.2 Hz, 1H), 3.76 (d, J = 9.8 Hz, 6H), 3.30 (s, 3H). 13C{1H} NMR
(100 MHz, DMSO) δ (ppm) 165.9, 159.8, 159.1, 152.6, 149.4, 146.2, 136.5, 130.2, 129.4, 121.3, 118.8, 115.3,
o
114.1, 112.9, 112.8, 100.3, 55.6, 55.5, 54.4, 51.2. HPLC: Chiracel AD-H column, 254 nm, 30 C, hexane/i-
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propanol = 70/30, flow = 0.8 mL/min, retention time 14.0 min(maj) and 17.0 min. HRMS (ESI) m/z Calculated
for C20H21N2O5 [M+H]+ 369.1445, found 369.1443.
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compound, white solid, mp: 227-228 C, Rf = 0.60 (dichloromethane/methanol = 30/1), 91% ee, [α]20
=
D
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+24.68 (c 0.62, MeOH). 1H NMR (400 MHz, CDCl3) δ (ppm) 7.30-7.09 (m, 10H), 6.15 (s, 1H), 5.40 (d, J =
2.9 Hz, 1H), 3.39 (s, 3H), 2.35 (s, 6H). 13C{1H} NMR (100 MHz, CDCl3) δ (ppm) 165.2, 152.3, 146.9, 142.8,
138.0, 137.5, 134.3, 129.9, 128.4, 128.2, 127.9, 127.6, 126.7, 124.7, 123.1, 101.3, 55.3, 50.6, 21.1, 20.8. HPLC:
o
Chiracel AD-H column, 254 nm, 30 C, hexane/i-propanol = 80/20, flow = 0.7 mL/min, retention time 11.5
min(maj) and 15.8 min. HRMS (ESI) m/z Calculated for C20H21N2O3 [M+H]+ 337.1547, found 337.1551.
tert-Butyl (R)-2-oxo-4,6-diphenyl-1,2,3,4-tetrahydropyrimidine-5-carboxylate (2j): 68 mg, 97% yield, new
o
compound, white solid, mp: 166-167 C, Rf = 0.50 (dichloromethane/ethyl acetate = 4/1), 94% ee, [α]20
=
D
+32.50 (c 0.68, MeOH). 1H NMR (400 MHz, CDCl3) δ (ppm) 7.43-7.21 (m, 11H), 6.10 (s, 1H), 5.42 (s, 1H),
1.04 (s, 9H). 13C{1H} NMR (100 MHz, CDCl3) δ (ppm) 164.7, 153.0, 145.6, 143.4, 135.5, 129.3, 128.8, 128.2,
128.1, 127.9, 126.6, 104.0, 80.4, 56.1, 27.6. HPLC: Chiracel AD-H column, 254 nm, 30 oC, hexane/i-propanol
= 80/20, flow = 0.7 mL/min, retention time 9.6 min(maj) and 11.6 min. HRMS (ESI) m/z Calculated for
C20H23N2O3 [M+H]+ 351.1703, found 351.1704.
(R)-N,N-diethyl-2-oxo-4,6-diphenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide (2k): 68 mg, 97% yield,
new compound, white solid, mp: 266-267 oC, Rf = 0.35 (ethyl acetate), 95% ee, [α]20D = -46.23 (c 1.22, MeOH).
1H NMR (400 MHz, CDCl3) δ (ppm) 7.38-7.21 (m, 12H), 5.74 (s, 1H), 5.62 (s, 1H), 3.90-2.94 (m, 2H), 2.37
(d, J = 55.5 Hz, 2H), 0.69 (t, J = 6.9 Hz, 3H), -0.07 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ (ppm) 167.3,
154.0, 141.9, 133.5, 131.5, 129.6, 128.7, 128.5, 128.1, 127.5, 126.8, 106.5, 59.0, 41.6, 37.5, 11.9, 11.5. HPLC:
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Chiracel AD-H column, 254 nm, 30 C, hexane/i-propanol = 80/20, flow = 0.8 mL/min, retention time 13.9
min and 16.1 min(maj). HRMS (ESI) m/z Calculated for C21H24N3O2 [M+H]+ 350.1863, found 350.1859.
Ethyl (R)-4,6-dimethyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (2l): 39 mg, 97% yield, known
1
compound,18 white solid, Rf = 0.45 (ethyl acetate), 36% ee, [α]20 = -54.51 (c 0.62, MeOH). H NMR (400
D
MHz, DMSO) δ (ppm) 4.13-4.06 (m, 3H), 2.16 (s, 3H), 1.19 (t, J = 7.1 Hz, 3H), 1.10 (d, J = 6.2 Hz, 3H).
13C{1H} NMR (100 MHz, DMSO) δ (ppm) 165.8, 152.9, 148.1, 100.9, 59.5, 46.7, 23.8, 18.1, 14.7. HPLC:
o
Chiracel AD-H column, 254 nm, 30 C, hexane/i-propanol = 80/20, flow = 0.7 mL/min, retention time 7.8
min(maj) and 8.6 min.
GeneralProcedure for Hydrogenation of Pyrimidin-2-ols 5:
A mixture of 2-hydroxypyrimidine 1 (0.20 mmol), dihydrophenanthridine (DHPD) 4d (36 mg, 0.20 mmol,
1 equiv), and chiral phosphoric acid (R)-3f (7.5 mg, 0.01 mmol, 5 mol %) in Benzene (4 mL) was stirred at 40
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oC under nitrogen for 24 h. The mixture was then cooled to room temperature, DHPD 4d (36 mg, 0.20 mmol,
1 equiv) was added again under the nitrogen atomsphere. The reaction mixture was replaced into the oil bath
at 40 oC under nitrogen for another 24 h.After the reaction was completed (determined by TLC), the solvent
was removed under reduced pressure. The residue was purified by flash chromatography on silica gel to yield
desire product. The enantiomeric excesses were determined by chiral HPLC. Racemates of 6 were prepared
by the reduction of 5 using the racemic catalyst.
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Ethyl 4-methyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxylate (6a): 47 mg, 90% yield, known
compound,18white solid, Rf = 0.40 (hexanes/ethyl acetate = 1/2), 77% ee, [α]20D = +102.90 (c 0.62, MeOH).
1H NMR (400 MHz, CDCl3) δ (ppm) 7.43-7.28 (m, 5H), 6.67 (s, 1H), 5.55 (s, 1H), 4.56-4.55 (m, 1H), 3.95
(q, J = 7.1 Hz, 2H), 1.45 (d, J = 6.3 Hz, 3H), 0.93 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ
(ppm) 165.4, 153.3, 146.7, 135.3, 129.5, 128.3, 127.9, 103.7, 60.0, 48.2, 23.6, 13.6. HPLC: Chiracel OD-H
column, 254 nm, 30 oC, hexane/i-propanol = 90/10, flow = 0.7 mL/min, retention time 13.5 min and 14.8 min
(maj).
Ethyl 6-(3-chlorophenyl)-4-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (6b): 54 mg, 92%
yield, new compound, white solid, mp: 205-206 oC, Rf = 0.40 (hexanes/ethyl acetate = 1/2), 76% ee, [α]20
=
D
+84.55 (c 0.68, MeOH). 1H NMR (400 MHz, CDCl3) δ (ppm) 7.42-7.12 (m, 5H), 5.92 (s, 1H), 4.42-4.40 (m,
1H), 3.92-3.85 (m, 2H), 1.33 (d, J = 6.4 Hz, 3H), 0.87 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3)
δ (ppm) 164.6, 153.5, 144.9, 136.1, 133.3, 128.9, 128.1, 125.9, 103.5, 59.6, 47.4, 23.0, 13.1. HPLC: Chiracel
OD-3 column, 254 nm, 30 oC, hexane/i-propanol = 90/10, flow = 0.9 mL/min, retention time 9.6 min and 10.6
min (maj). HRMS (ESI) m/z Calculated for C14H16ClN2O3 [M+H]+ 295.0844, found 295.0848.
Ethyl 6-(3-bromophenyl)-4-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (6c): 61 mg, 90%
yield, new compound, white solid, mp: 199-200 oC, Rf = 0.35 (hexanes/ethyl acetate = 1/2), 78% ee, [α]20
=
D
+73.93 (c 1.22, MeOH). 1H NMR (400 MHz, CDCl3) δ (ppm) 7.83 (s, 1H), 7.54-7.52 (m, 1H), 7.45 (s, 1H),
7.28-7.25 (m, 2H), 6.23 (s, 1H), 4.45 (d, J = 5.3 Hz, 1H), 3.99-3.91 (m, 2H), 1.41 (d, J = 6.3 Hz, 3H), 0.95 (t,
J = 7.1 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ (ppm) 164.6, 153.3, 144.7, 136.3, 131.8, 130.9, 129.1,
126.3, 121.4, 103.6, 59.6, 47.4, 23.1, 13.2. HPLC: Chiracel OD-3 column, 254 nm, 30 oC, hexane/i-propanol
= 90/10, flow = 0.9 mL/min, retention time 10.1 min and 10.8 min (maj). HRMS (ESI) m/z Calculated for
C14H16BrN2O3 [M+H]+ 339.0339, found 339.0342.
Ethyl 6-(3-methoxyphenyl)-4-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (6d): 52 mg, 90%
yield, new compound, white solid, mp: 232-233 oC, Rf = 0.40 (hexanes/ethyl acetate = 1/2), 75% ee, [α]20
=
D
+102.71 (c 0.70, MeOH). 1H NMR (400 MHz, CDCl3) δ (ppm) 7.60 (s, 1H), 7.29-7.25 (m, 1H), 6.94-6.83 (m,
3H), 6.41 (s, 1H), 4.44-4.41 (m, 1H), 3.97-3.91 (m, 2H), 3.80 (s, 3H), 1.41 (d, J = 6.3 Hz, 3H), 0.95 (t, J = 7.1
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Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ (ppm) 165.5, 159.3, 153.9, 146.6, 136.3, 129.2, 120.5, 115.2,
113.4, 103.5, 59.9, 55.3, 47.9, 23.5, 13.7. HPLC: Chiracel AD-H column, 254 nm, 30 oC, hexane/i-propanol
= 90/10, flow = 0.7 mL/min, retention time 22.2 min and 24.6 min (maj). HRMS (ESI) m/z Calculated for
C15H19N2O4 [M+H]+ 291.1339, found 291.1341.
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Ethyl 6-(4-methoxyphenyl)-4-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (6e): 53 mg, 91%
yield, new compound, white solid, mp: 214-215 oC, Rf = 0.40 (hexanes/ethyl acetate = 1/2), 79% ee, [α]20
=
D
1
+81.92 (c 0.78, MeOH). H NMR (400 MHz, CDCl3) δ (ppm) 7.60 (brs, 1H), 7.28-7.25 (m, 2H), 6.91-6.89
(m, 2H), 6.18 (brs, 1H), 4.45 (s, 1H), 4.00-3.96 (m, 2H), 3.80 (s, 3H), 1.39 (d, J = 6.3 Hz, 3H), 0.94 (t, J = 7.1
Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ (ppm) 165.6, 160.6, 153.8, 146.8, 129.6, 127.1, 113.5, 103.0,
59.9, 55.3, 48.0, 23.5, 13.9. HPLC: Chiracel OD-3 column, 254 nm, 30 oC, hexane/i-propanol = 90/10, flow
= 0.9 mL/min, retention time 14.7 min and 17.0 min (maj). HRMS (ESI) m/z Calculated for C15H19N2O4
[M+H]+ 291.1339, found 291.1334.
Ethyl 4-methyl-2-oxo-6-(m-tolyl)-1,2,3,4-tetrahydropyrimidine-5-carboxylate (6f): 52 mg, 95% yield, new
compound, white solid, mp: 240-241 oC, Rf = 0.40 (hexanes/ethyl acetate = 1/2), 75% ee, [α]20D = +90.22 (c
0.90, MeOH). 1H NMR (400 MHz, CDCl3) δ (ppm) 7.20-7.01 (m, 5H), 6.03 (brs, 1H), 4.40 (s, 1H), 3.89-3.83
(m, 2H), 2.28 (s, 3H), 1.33 (d, J = 4.8 Hz, 3H), 0.84 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ
(ppm) 165.5, 153.5, 147.0, 137.9, 135.1, 130.2, 128.6, 128.1, 125.1, 103.4, 59.9, 48.0, 23.6, 21.3, 13.7. HPLC:
Chiracel OD-3 column, 254 nm, 30 oC, hexane/i-propanol = 90/10, flow = 0.9 mL/min, retention time 9.8 min
and 11.0 min (maj). HRMS (ESI) m/z Calculated for C15H19N2O4 [M+H]+ 275.1390, found 275.1387.
Hydrogenation of Pyrimidin-2-ols at Gram Scale: A mixture of Pyrimidin-2-ols 1a (1.282 g, 4.0 mmol),
Hantzsch ester 4a (1.216 g, 4.8 mmol, 1.2 equiv), and chiral phosphoric acid (R)-3f (151 mg, 0.2 mmol, 5
o
mol %) in Toluene (40 mL) was stirred at 40 C under nitrogen for 24 h. After the reaction was completed
(determined by TLC). The resulting mixture was concentrated in vacuo and further purification was performed
by a silica gel column eluted with ethyl acetate/methanol to give thehydrogenation product (R)-(+)-2a 1.268
g in 98% yield and 94% ee.
Synthesis of the Chiral Cyclic Thiourea: According to the known report:19 To a solution of cyclic urea
(R)-(+)-2a (> 99% ee after recrystallization, 65 mg, 0.20 mmol) in anhydrous toluene (4.0 mL) was added
Lawesson’s reagent (97 mg, 0.24 mmol) under nitrogen atmosphere. The resulting solution was refluxed
overnight. Toluene was removed in vacuo and the residue was diluted with water. The aqueous mixture was
extracted with dichloromethane (15 mL×3). The combined organic layer was washed twice with brine, dried
over anhydrous sodium sulfate, and concentrated under reduced pressure to give viscous oil. The crude product
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was purified by flash column chromatography using dichloromethane/methanol as eluent to give the chiral
thiourea 65 mg.
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Ethyl (R)-4,6-diphenyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (8a): 65 mg, 96% yield,
known compound,20 white solid, > 99% ee, [α]20D = -7.98 (c 0.94, MeOH), Rf = 0.40 (hexanes/ethyl acetate =
1/2). 1H NMR (400 MHz, CDCl3) δ (ppm) 7.82 (brs, 1H), 7.45-7.33 (m, 10H), 5.58 (s, 1H), 3.94-3.84 (m, 2H),
0.86-0.83 (m, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ (ppm) 174.5, 164.8, 143.9, 142.1, 134.0, 129.9, 129.0,
128.5, 128.4, 128.1, 126.9, 103.7, 60.4, 56.4, 13.5. HPLC: Chiracel AD-H column, 254 nm, 30 oC, hexane/i-
propanol = 90/10, flow = 0.9 mL/min, retention time 16.6 min (maj) and 18.3 min.
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ASSOCIATED CONTENT
Supporting information
NMR spectra of products, and HPLC for racemic and chiral products of all compounds. This material is
available free of charge via the internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding author
*E-mail: shileichem@dlut.edu.cn
*E-mail:ygzhou@dicp.ac.cn
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We are grateful for the financial support from the National Natural Science Foundation of China (21772195,
21532006) and the Strategic Priority Program of Chinese Academy of Sciences (XDB17020300) is
acknowledged.
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