Facile Synthesis of Chiral Cyclic Ureas through Hydrogenation of 2-Hydroxypyrimidine/Pyrimidin-2(1H)-one Tautomers

Article abstract of DOI:10.1002/anie.201801485

A facile access to optically active cyclic ureas was developed through palladium-catalyzed asymmetric hydrogenation of pyrimidines containing tautomeric hydroxy group with up to 99 % ee. Mechanistic studies indicated that reaction pathway proceed through

Full text of DOI:10.1002/anie.201801485

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: Facile synthesis of chiral cyclic ureas via hydrogenation of
pyrimidines containing tautomeric hydroxyl group
Authors: Yong-Gui Zhou, Guang-Shou Feng, Mu-Wang Chen, and Lei
Shi
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201801485
Angew. Chem. 10.1002/ange.201801485
Link to VoR: http://dx.doi.org/10.1002/anie.201801485
http://dx.doi.org/10.1002/ange.201801485

10.1002/anie.201801485
Angewandte Chemie International Edition
COMMUNICATION
Facile Synthesis of Chiral Cyclic Ureas via Hydrogenation of
Pyrimidines Containing Tautomeric Hydroxyl Group**
Guang-Shou Feng,[a][b] Mu-Wang Chen,[a] Lei Shi*[a] and Yong-Gui Zhou*[a]
Abstract: A facile access to optically active cyclic ureas was
developed through palladium-catalyzed asymmetric hydrogenation
of pyrimidines containing tautomeric hydroxyl group with up to 99%
ee. Mechanistic studies indicated that reaction pathway proceed
through hydrogenation of C=N of the oxo tautomer pyrimidin-2(1H)-
one, acid-catalyzed isomerization of enamine-imine, and hydrogen-
ation of imine pathway. In addition, the chiral cyclic ureas are readily
converted into useful chiral 1,3-diamine and thiourea derivatives
without loss of optical purity.
derivatives via an organocatalytic tandem aza-Michael addition-
hemiaminal formation and dehydroxylation cascade was
successfully developed by Chen and co-workers.[6] Very
recently, Rovis’ group developed an elegant rhodium-catalyzed
[4+2] cycloaddition between α,β-unsaturated imines and
isocyanates to generate the chiral DHPMs in good yields and
high enantioselectivities.[7] Despite these successful examples,
given the great importance of chiral cyclic ureas, it remains
indispensable to find new effective approaches to prepare
structurally diverse chiral cyclic ureas derivatives with excellent
enantioselectivity.
Ureas are commonly found in biologically active compounds,
pharmaceuticals, agricultural pesticides, dyes for cellulose fibers,
antioxidants in gasoline, as well as chiral catalysts for organic
synthesis.[1] Especially, as an important pharmacophore, cyclic
urea skeleton has been widely embedded in many bioactive
molecules and pharmaceutical agents, such as calcium channel
blocker SQ32926,[1d] tubulin inhibitors PPB-SOs[1e] and α1a-
receptor antagonist (S)-L-771688[1f] (Figure 1).
Figure 1. Selected bioactive molecules containing cyclic urea motifs.
Traditional syntheses of the chiral ureas often use phosgene
or isocyanates which cause tremendous toxicological and
environmental problems.[2] The development of environment-
tally friendly methods to prepare urea-containing compounds
without using harmful reagents has attracted considerable
attention and obtained certain achievements.[3] However, there
are only a few reports on direct asymmetric synthesis of chiral
cyclic ureas (Scheme 1). In 2005, Zhu and co-workers
described an asymmetric catalytic Biginelli reaction with a chiral
ytterbium catalyst, providing chiral cyclic ureas, 3,4-dihydro-
pyrimidinones (DHPMs) in high yields with excellent enantiose-
lectivities.[4] Shortly after, Gong and co-workers reported the
first asymmetric organocatalytic Biginelli reaction catalyzed by
a BINOL-derived chiral phosphoric acid catalyst, affording the
chiral DHPMs in high enantioselectivity.[5] Notably, in 2010, a
method for the asymmetric synthesis of chiral cyclic urea
Scheme 1. Catalytic asymmetric synthesis of chiral cyclic ureas.
Asymmetric hydrogenation of heteroaromatics is one of
efficient methods for synthesis of chiral heterocycles. Although
catalytic asymmetric hydrogenation of heteroarenes has been
well documented,[8] most successful examples in this field are
limited to bicyclic and a few of monocyclic heteroaromatic
compounds.[9] Particularly, six-membered N-aromatics, such as
pyridine, pyrimidine, pyrazine and so on, still remain challenging.
Considering tautomerism of N-heteroarenes containing potential
tautomeric functional group (OH, SH, NHR, acylmethyl, etc) is
intimately relative to the aromaticity, chemical reactivity[9k, 9l] and
biological activity.[10] Introducing a hydroxyl substituent on α or 
to pyridine-like nitrogen atom of N-heteroarene leads to the
hydroxyl-oxo tautomerism to weaken aromaticity. This property
might supply a potential solution for enantioselective hydrogen-
ation of those heteroarenes with high stability. Tautomeric
equilibria for 2- and 4-hydroxypyrimidines in gas or solution
phase has been well studied in detail.[10a,11] As such, in most
solvents, the lactam-lactim equilibrium of 2-hydroxypyrimidine
is more toward the oxo form in pyrimidine-2(1H)-one. This oxo
tautomer preserves aromatic character but lower than hydroxyl
tautomer. Thus, it is reasonable to envision that oxo tautomer
[a]
G.-S. Feng, M.-W Chen, Prof. L. Shi, Prof. Y.-G. Zhou
State Key Laboratory of Catalysis
Dalian Institute of Chemical Physics, Chinese Academy of Sciences
Dalian 116023, China
E-mail: shileichem@dicp.ac.cn
E-mail: ygzhou@dicp.ac.cn
[b]
G.-S. Feng
University of Chinese Academy of Sciences, Beijing 100049, China
[**] Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/anie.201801485
Angewandte Chemie International Edition
COMMUNICATION
with lower aromaticity might be amenable to asymmetric
hydrogenation condition, giving the chiral cyclic ureas (Scheme
1). To the best of our knowledge, only one successful example
on asymmetric hydrogenation of pyrimidines was reported by
Kuwano group.[12] Substoichiometric achiral Lewis acid was
employed to promote the hydrogenation of pyrimidines.
Interestingly, chiral cyclic amidines as the reduced product were
obtained with excellent enantioselectivities and yields. Herein,
used. 1a could be hydrogenated in full conversion to give the
chiral cyclic urea 2a with poor 26% ee (entry 3). It is noteworthy
that the reactivity decreased in the absence of Brønsted acid
(entry 4). Next, various acid additives were tested and gave
similar ee values in the range of 25-31% (entries 5-8). Next, we
tested the effect of some commercially available bisphosphine
ligands on reactivity and enantioselectivity (entries 9-11). It was
turned out that electron-donating ferrocene-derived Josiphos-
type ligand (R,S)-PPF-PtBu2 (L4) was the best in view of both
reactivity and enantioselectivity (entry 11). Delightedly, elevating
the temperature to 80 oC afforded slightly higher 94% of
enantioselectivity (entry 12). Thus, the optimized conditions
were established as: Pd(OCOCF3)2 (3.0 mol%)/(R,S)-PPF-PtBu2
(3.3 mol%)/PhCO2H (10 mol%)/TFE/H2 (1000 psi)/80 oC.
we report
a
highly enantioselective palladium-catalyzed
hydrogenation of pyrimidines containing tautomeric hydroxyl
group, giving the chiral cyclic ureas with up to 99% of
enantioselectivity.
Table 1. Condition optimization.[a]
OH
O
Pd(OCOCF3)2 (3.0 mol%)
(R,S)-PPF-PtBu2 (3.3 mol%)
H2
(1000 psi)
N
HN
NH
N
+
PhCO2H (10 mol%)
R
R
TFE, 80 o
C
1
2
O
O
O
O
HN
NH
HN
NH
HN
NH
HN
NH
2ab
2b
2c
2d
entry
1
solvent
PhMe
THF
TFE
TFE
TFE
TFE
TFE
TFE
TFE
TFE
TFE
TFE
additive
TFA
ligand
L1
L1
L1
L1
L1
L1
L1
L1
L2
L3
L4
L4
conv. (%)[b]
<5
ee (%)[c]
NA
93% yield, 90% ee
93% yield, 96% ee 82% yield, 93% ee
90% yield, 95% ee
O
O
O
O
HN
NH
HN
NH
HN
NH
HN
NH
2
TFA
<5
NA
OMe
OMe
3
TFA
>95
26 (S)
32 (S)
31 (S)
25(S)
30 (S)
30 (S)
36 (R)
74 (R)
89 (R)
94 (R)
n-Pr
CF3
4
--
83
OMe
2e
2f
2g
2h
5
PhCO2H
TsOH·H2O
(D)-CSA
(L)-CSA
PhCO2H
PhCO2H
PhCO2H
PhCO2H
>95
92% yield, 92% ee
95% yield, 94% ee
96% yield, 87% ee 92% yield, 94% ee
6
>95
O
O
O
O
7
>95
NH
HN
NH
HN
NH
HN
NH
HN
8
>95
O
9
>95
F
2i
2j
2k
2l
95% yield, 93% ee
94% yield, 86% ee
96% yield, 72% ee 95% yield, 80% ee
10
11
12[d]
>95
>95
Scheme 2. Pd-catalyzed Asymmetric Hydrogenation of 2-Hydroxypyrimidines
1.[a] [a] Conditions: 2-hydroxypyrimidines 1 (0.30 mmol), Pd(OCOCF3)2 (3.0
mol%), L4 (R,S)-PPF-PtBu2 (3.3 mol%), PhCO2H (10 mol%), H2 (1000 psi),
TFE (3.0 mL), 80 oC, 24 h, [b] 5.9 mmol scale.
>95 (91)[e]
[a] Conditions: 1a (0.20 mmol), Pd(OCOCF3)2 (3.0 mol%), ligand (3.3
mol%), additive (10 mol%), H2 (1000 psi), solvent (3.0 mL), 24 h, 60 oC. [b]
Determined by 1H NMR spectroscopy. [c] Determined by HPLC analysis of
the corresponding N-benzoyl derivatives. [d] 80 oC. [e] Isolated yield.
With the optimal condition in hand, we next examined the
substrate scope, and the results are summarized in Scheme 2.
A series of 4-aryl substituted 2-hydroxypyrimidines could be
hydrogenated smoothly, giving the corresponding chiral cyclic
ureas with excellent yields and excellent enantioselectivities (2a-
2j). This reaction is not sensitive to the electronic character or
steric hindrance effect of the substituent on C4 aromatic ring,
and the corresponding products were obtained in 82-96% yields
and 86−96% ee. Furthermore, the asymmetric hydrogenation of
1k possessing the heterocyclic ring substituent proceeded with
full conversion and moderate 72% ee (2k). Fortunately, 4-alkyl
2-hydroxypyrimidine can also give the corresponding chiral
cyclic urea in moderate 80% ee (2l) under the standard
condition. It was noteworthy that the gram scale experiment of
1a was performed under the standard condition without loss of
reactivity (90% vs 91% yield) and enantioselectivity (95% ee vs
94% ee).
Under the assumption that the oxo form of the 2-hydroxy-
pyrimidine tautomer is more reactive due to its relatively lower
aromaticity, we started the investigation of a proper asymmetric
hydrogenation catalyst system for this concept. Previous
research have demonstrated that Brønsted acids often play as
promoter to facilitate the hydrogenation through activating
substrate[13] and accelerating imine-enamine[9f] or hydroxyl-oxo
tautomerization.[14] In addition, much progresses have been
successfully achieved in palladium-catalyzed asymmetric hydro-
genation, which feature a robust hydrogenation catalyst with
high toleration to the strong Brønsted acid, oxygen and
moisture.[15-17] Thus, initially, we choose readily available 4-
phenylpyrimidin-2-ol (1a) as model substrate, Pd(OCOCF3)2 /(S)-
Synphos (L1) complex as hydrogenation catalyst and
trifluoroacetic acid (TFA) as additive. The hydrogenation was run
in toluene at 60 °C under 1000 psi of hydrogen. Disappointedly,
hydrogenation did not occur (Table 1, entry 1). Subsequently,
the solvent effect was examined (entries 1-3). The reaction
Encouraged by these results obtained, we turned our attention
to more complex di- and trisubstituted 2-hydroxypyrimidines.
After a slightly modification of condition (using more acidic
phosphoric acid instead of benzoic acid), this strategy turned out
to be successful, and a range of disubstituted 2-hydroxypyrimi-
experienced significant solvent effects and
a
dramatic
enhancement was observed when trifluoroethanol (TFE) was
This article is protected by copyright. All rights reserved.

10.1002/anie.201801485
Angewandte Chemie International Edition
COMMUNICATION
dines (4a-4e, Scheme 3) could be well hydrogenated in the
presence of chiral phosphoric acid with high diastereoselec-
tivities and 68-92% of enantioselectivities. Notably, asymmetric
hydrogenation of trisubstituted 2-hydroxypyrimidines 3f-3h
furnished the partial hydrogenation 3,4-dihydropyrimidinones 4f-
4h in 92-98% yield and 93-99% of enantioselectivities.[18] It
should be noted that the configuration of BINOL-derived chiral
phosphoric acid would not affect the enantioselectivity and
absolute configuration (see table 1 in Support Information).
explore the mechanism, the hydrogenation reaction of 1a was
carried out and was stopped just after 4 hours. Gratifyingly, H
NMR analysis of the crude hydrogenation mixture showed the
existence of partially hydrogenation intermediate enamine 8 with
1H NMR and HRMS.
1
Scheme 5. Proposed reaction pathway.
Based on the above experimental results, a plausible stepwise
hydrogenation process was proposed (Scheme 5). In the
reaction system, the 2-hydroxypyrimidine mainly exists in two
tautomeric oxo forms 6 and 7. Firstly, the N1-C6 double bond of
7 is hydrogenated to give the intermediate dihydropyrimidin-
2(1H)-one 8. Next, the intermediate 8 proceeds the acid-
catalyzed tautomerization process of enamine to imine 9,
followed by palladium-catalyzed asymmetric hydrogenation of
imine 9 to give the final chiral cyclic urea 2a.
Scheme 3. Palladium-catalyzed asymmetric hydrogenation of di- and trisub-
stituted 2-hydroxypyrimidines. [a] Pd(OCOCF3)2 (5.0 mol%), (R,S)-PPF-PtBu2
(5.5 mol%) was used instead of L5, PhCO2H (10 mol%) was used instead of
(S)-CPA, H2 (1200 psi), TFE (3.0 mL), 100 oC, 72 h.
Scheme 6. Product elaboration: synthesis of chiral 1,3-diamine and cyclic
thiourea.
After establishing the facile approach for the synthesis of
chiral cyclic ureas by asymmetric hydrogenation, we further
evaluated the practical utility (Scheme 6). Firstly, the ring
opening experiments of products have been conducted.
According to the reported method, cleavage of the urea failed to
give the free diamines under acidic conditions.[3b] Fortunately,
the chiral cyclic urea 2a can be readily protected with benzyl
bromide, followed by reduction by LiAlH4 and hydrolysis could
provide the desired chiral 1,3-diamine 11 with 93% ee.[19] This
result demonstrated direct synthesis of important chiral 1,3-
diamine skeleton and may deliver practical application in
enantioselective synthesis, organocatalysis, and medicinal
chemistry.[20] Significantly, treatment of the 2a with Lawesson's
reagent afforded chiral cyclic thiourea 12 without loss of optical
purity (Scheme 6). [21]
In summary, an efficient palladium-catalyzed asymmetric hy-
drogenation of 2-hydroxypyrimidines has been successfully
developed for the facile synthesis of chiral cyclic ureas with up to
99% ee. The current catalytic system exhibits an impressive
broad substrate scope, mono-, di- and trisubstituted 2-
hydroxypyrimidines can be easily hydrogenated with good yields
and enantioselectivities. The practicability of the reaction has
been demonstrated by the easy scalability and synthesis of
Scheme 4. Mechanistic investigation.
To gain insight into the mechanism of this reaction, some
control experiments were carried out (Scheme 4). As expected,
no reaction was observed for the hydroxyl protected substrate 5
(eq. 1). When the isotopic labeling experiment was carried out
by the reaction of 1a with D2, the deuterium atoms were
incorporated on the C4 and C6 position (>95% and >95%) (eq.
2). The above result suggested that asymmetric hydrogenation
of imine happened twice on C4 and C6, respectively. Then, the
hydrogenation of 1a was carried out in d3-TFE (eq. 3), H NMR
1
analysis of the crude hydrogenation product showed that the
deuterium atoms were taken up to C5 with >95% incorporation,
which was possibly caused by the fast enamine-imine
tautomerization during hydrogenation process. To further
This article is protected by copyright. All rights reserved.

10.1002/anie.201801485
Angewandte Chemie International Edition
COMMUNICATION
Glorius, Synlett. 2015, 26, 1557-1562; l) K. Higashida, H. Nagae, K.
Mashima, Adv. Synth. Catal. 2016, 358, 3949-3954.
important chiral 1,3-diamines and cyclic thioureas. Further
investigations on the hydrogenation of related challenging
heteroaromatic compounds are ongoing in our laboratory.
[10] a) B. Stanovnik, M. Tišler, A. R. Katritzky, O. V. Denisko. Adv.
Heterocycl. Chem. 2006, 91, 1-134; b) A. T.Balaban, D. C.Oniciu, A. R.
Katritzky, Chem. Rev. 2004, 104, 2777-2812; c) E. D. Raczyńska, W.
Kosińska, B. Ośmiałowski, R. Gawinecki, Chem. Rev. 2005, 105, 3561-
3612; d) E. D. Raczyńska, J. Theor. Comput. Chem. 2014, 1042, 8-15.
[11] a) M. Chevrier, O. Bensaude, J. Guillerez, J. E. Dubois, Tetrahedron
Lett. 1980, 21, 3359-3362; b) P. Cieplak, M. Geller, J. Mol. Struc.
Theochem. 1985, 124, 249-259; c) C. Kashima, A. Katoh, M. Shimizu,
Y. Omote, Heterocycles 1984, 22, 2591-2594; d) P. Beak, F. S. J. Fry,
J. Lee, F. Steele, J. Am. Chem. Soc. 1976, 98, 171-179.
Acknowledgements
Financial support from the National Natural Science Foundation
of China (21772195, 21532006), Chinese Academy of Sciences
(QYZDJ-SSW-SLH035), Dalian Bureau of Science and Technol-
ogy (2016RD07) and the strategic priority program of Chinese
Academy of Sciences (XDB17020300) is acknowledged.
[12] a) R. Kuwano, Y. Hashiguchi, R. Ikeda, K. Ishizukae, Angew. Chem. Int.
Ed. 2015, 54, 2393-2396; Angew. Chem. 2015, 127, 2423-2426.
[13] a) For the selected reports, see 9c, and see also: a) M.-W. Chen, Z.-S.
Ye, Z.-P. Chen, B. Wu, Y.-G. Zhou, Org. Chem. Front. 2015, 2, 586-
589; b) A. Iimuro, K. Yamaji, S. Kandula, T. Nagano, Y. Kita, K.
Mashima, Angew. Chem., Int. Ed. 2013, 52, 2046-2050; Angew. Chem.
2013, 125, 2100-2104.
Keywords: asymmetric hydrogenation • pyrimidine • palladium
•tautomerization• chiral cyclic urea • 1,3-diamine
[1]
a) I. Gallou, Org. Prep. Proced. Int. 2007, 39, 355-383; b) K. Matsuda,
Med. Res. Rev. 1994, 14, 271-305; c) N. C. Desai, M. T. Chhabaria, A.
Dodiya, A. M. Bhavsar, B. B. Baldaniya, Med. Chem. Res. 2010, 20,
1331-1339; d) K. S. Atwal, B. N. Swanson, S. E. Unger, D. M. Floyd, S.
Moreland, A. Hedberg, B. C. O’Reilly, J. Med. Chem. 1991, 34, 806-811;
e) S. Fortin, L. Wei, E. Moreau, J. Lacroix, M.-F. Côté, É. Petitclerc, L.
P. Kotra, R. C. Gaudreault, J. Med. Chem. 2011, 54, 4559-4580; f) J. C.
Barrow, P. G. Nantermet, H. G. Selnick, K. L. Glass, K. E. Rittle, K. F.
Gilbert, T. G. Steele, C. F. Homnick, R. M. Freidinger, R. W. Ransom, P.
Kling, D. Reiss, T. P. Broten, T. W. Schorn, R. S. L. Chang, S. S.
O'Malley, T. V. Olah, J. D. Ellis, A. Barrish, K. Kassahun, P. Leppert, D.
Nagarathnam, C. Forray, J. Med. Chem. 2000, 43, 2703-2718.
a) H. Babad, A. G. Zeiler, Chem. Rev. 1973, 73, 75-91; b) F. Bigi, R.
Maggi, G. Sartori, Green Chem. 2000, 2, 140-148.
[14] Z.-P. Chen, M.-W. Chen, L. Shi, C.-B. Yu, Y.-G. Zhou, Chem. Sci. 2015,
6, 3415-3419.
[15] For reviews on Pd-catalyzed asymmetric hydrogenation, see: a) Q.-A.
Chen, Z.-S. Ye, Y. Duan, Y.-G. Zhou, Chem. Soc. Rev. 2013, 42, 497-
511; b) J. Xie, Q. Zhou, Acta Chim. Sinica 2012, 70, 1427-1438.
[16] For selected examples, see: a) A. Suzuki, M. Mae, H. Amii, K.
Uneyama, J. Org. Chem. 2004, 69, 5132-5134; b) H. Abe, H. Amii, K.
Uneyama, Org. Lett. 2001, 3, 313-315; c) Y.-Q. Wang, C.-B. Yu, D.-W.
Wang, X.-B. Wang, Y.-G. Zhou, Org. Lett. 2008, 10, 2071-2074; d) C.-B.
Yu, D.-W. Wang, Y.-G. Zhou, J. Org. Chem. 2009, 74, 5633-5635; e)
M.-W. Chen, Y. Duan, Q.-A. Chen, D.-S. Wang, C.-B. Yu, Y.-G. Zhou,
Org. Lett. 2010, 12, 5075-5077; f) X.-Y. Zhou, M. Bao, Y.-G. Zhou, Adv.
Synth. Catal. 2011, 353, 84-88; g) Y. Duan, X.-Y. Zhu, J.-A. Ma, Y.-G.
Zhou, Tetrahedron Lett. 2013, 54, 6161-6163; h) Z.-P. Chen, S.-B. Hu,
J. Zhou, Y.-G. Zhou, ACS Catal. 2015, 5, 6086-6089; i) Z. Yan, B. Wu,
X. Gao, M.-W. Chen, Y.-G. Zhou, Org. Lett. 2016, 18, 692-695.
[17] For Pd-catalyzed asymmetric hydrogenation of heteroarenes, see 9f,
and see also: a) D.-S. Wang, Q.-A. Chen, W. Li, C.-B. Yu, Y.-G. Zhou,
X. Zhang, J. Am. Chem. Soc. 2010, 132, 8909-8911; b) D.-S. Wang, J.
Tang, Y.-G. Zhou, M.-W. Chen, C.-B. Yu, Y. Duan, G.-F. Jiang, Chem.
Sci. 2011, 2, 803-806; c) Y. Duan, L. Li, M.-W. Chen, C.-B. Yu, H.-J.
Fan, Y.-G. Zhou, J. Am. Chem. Soc. 2014, 136, 7688-7700; d) X.-F.
Cai, W.-X. Huang, Z.-P. Chen, Y.-G. Zhou, Chem. Commun. 2014, 50,
9588-9590.
[2]
[3]
a) Y. Nishikawa, S. Kimura, Y. Kato, N. Yamazaki, O. Hara, Org. Lett.
2015, 17, 888-891; b) M. Morgen, S. Bretzke, P. Li, D. Menche, Org.
Lett. 2010, 12, 4494-4497; c) S. H. Kim, S. H. Hong, Org. Lett. 2016, 18,
212-215.
[4]
[5]
[6]
Y. Huang, F. Yang, C. Zhu, J. Am. Chem. Soc. 2005, 127, 16386-
16387.
X.-H. Chen, X.-Y. Xu, H. Liu, L.-F. Cun, L.-Z. Gong, J. Am. Chem. Soc.
2006, 128, 14802-14803.
Z.-Q. He, Q. Zhou, L. Wu, Y.-C. Chen, Adv. Synth. Catal. 2010, 352,
1904-1908.
[7]
[8]
K. M. Oberg , T. Rovis, J. Am. Chem. Soc. 2011, 133, 4785-4787.
For reviews on hydrogenation of heteroaromatics, see: a) F. Glorius,
Org. Biomol. Chem. 2005, 3, 4171-4175; b) Y.-G. Zhou, Acc. Chem.
Res. 2007, 40, 1357-1366; c) R. Kuwano, Heterocycles 2008, 76, 909-
922; d) D.-S. Wang, Q.-A. Chen, S.-M. Lu, Y.-G. Zhou, Chem. Rev.
2012, 112, 2557-2590; e) Y.-M. He, F.-T. Song, Q.-H. Fan, Top. Curr.
Chem. 2014, 343, 145-190; f) B. Balakrishna, J. L. Núñez-Rico, A.
Vidal-Ferran, Eur. J. Org. Chem. 2015, 5293-5303; g) Z.-P. Chen, Y.-G.
Zhou, Synthesis 2016, 48, 1769-1781.
[18] When the trisubstituted ethyl 2-hydroxy-4-methyl-6-phenylpyrimidine-5-
carboxylate was subjected to asymmetric hydrogenation under the
standard condition, giving the mixture of two reduced products with 2:1
of ratio (ethyl 6-methyl-2-oxo-4-phenyl-1,2,3,4-tetrahydropyrimidine-5-
carboxylate vs ethyl 4-methyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrimi-
dine-5-carboxylate), and the ees of the two products were 37% and
89%, respectively. Notably, the two isomers could not be separated by
column chromatography.
[9]
a) For the selected examples on asymmetric hydrogenation of
monocyclic heteroaromatics, see: a) Z.-S. Ye, M.-W. Chen, Q.-A. Chen,
L. Shi, Y. Duan, Y.-G. Zhou, Angew. Chem. Int. Ed. 2012, 51, 10181-
10184; Angew. Chem. 2012, 124, 10328-10331; b) M. Chang, Y.
Huang, S. Liu, Y. Chen, S. W. Krska, I. W. Davies, X. Zhang, Angew.
Chem. Int. Ed. 2014, 53, 12761; Angew. Chem. 2014, 126, 12975-
12978; c) Y. Kita,; A. Iimuro, S. Hida, K. Mashima, Chem. Lett. 2014,
43, 284-286; d) C. Y. Legault, A. B. Charette, J. Am. Chem. Soc. 2005,
127, 8966-8967; e) W.-X. Huang, L.-J. Liu, B. Wu, G.-S. Feng, B. Wang,
Y.-G. Zhou, Org. Lett. 2016, 18, 3082-3085; f) D.-S. Wang, Z.-S. Ye,
Q.-A. Chen, Y.-G. Zhou, C.-B. Yu, H.-J. Fan, Y. Duan, J. Am. Chem.
Soc. 2011, 133, 8866-8869; g) R. Kuwano, M. Kashiwabara, M.
Ohsumi, H. Kusano, J. Am. Chem. Soc. 2008, 130, 808-809; h) R.
Kuwano, N. Kameyama, R. Ikeda, J. Am. Chem. Soc. 2011, 133, 7312-
7315; i) J. Wysocki, N. Ortega, F. Glorius, Angew. Chem. Int. Ed. 2014,
53, 8751-8755; Angew. Chem. 2014, 126, 8896-8900; j) M.-W. Chen, Y.
Ji, J. Wang, Q.-A. Chen, L. Shi, Y.-G. Zhou Org. Lett. 2017, 19,
4988−4991; For the pioneering work of tautomerization enhancing
reactivity of the heteroarenes, see: k) J. Wysocki, C. Schlepphorst, F.
[19] a) H. A. Bates, N. Condulis, N. L. Stein, J. Org. Chem. 1986, 51, 2228-
2229; b) A. R. Pradipta, K. Tanaka, Bull. Chem. Soc. Jpn. 2016, 89,
337-345.
[20] a) X. Ji, H. Huang, Org. Biomol. Chem. 2016, 14, 10557-10566; b) W. P.
Hems, M. Groarke, A. Zanotti-Gerosa, G. A. Grasa, Acc. Chem. Res.
2007, 40, 1340-1347.
[21] P. Thanigaimalai, K.-C. Lee, S.-C. Bang, J.-H. Lee, C.-Y. Yun, E. Roh,
B.-Y. Hwang, Y. Kim, S.-H. Jung, Bioorgan. Med. Chem. 2010, 18,
1135-1142.
This article is protected by copyright. All rights reserved.

10.1002/anie.201801485
Angewandte Chemie International Edition
COMMUNICATION
COMMUNICATION
Guang-Shou Feng, Mu-Wang Chen, Lei
Shi* and Yong-Gui Zhou*
Page No. – Page No.
Facile Synthesis of Chiral Cyclic
Ureas via Hydrogenation of
Pyrimidines Containing Tautomeric
Hydroxyl Group
An enantioselective palladium-catalyzed hydrogenation of pyrimidines containing
tautomeric hydroxyl group is described. This methodology provides a convenient
route to chiral cyclic ureas with up to 99% ee. The cyclic chiral ureas are readily
converted into useful chiral 1,3-diamine and thiourea derivatives without loss of
optical purity.
This article is protected by copyright. All rights reserved.