ZrCl4-catalyzed nucleophilic dearomatization of 2-hydroxy-pyrimidines: A concise synthesis of novel 3,4-dihydropyrimidin-2(1H)-ones containing a phosphonic ester group

Article abstract of DOI:10.1016/j.tetlet.2021.153149

Catalytic nucleophilic dearomatization of 2-hydroxypyrimidines with phosphites was effectively achieved by utilizing ZrCl₄ as the catalyst under mild conditions. This new methodology presents a direct synthesis of 3,4-dihydropyrimidin-2(1H)-one

Full text of DOI:10.1016/j.tetlet.2021.153149

Tetrahedron Letters 73 (2021) 153149
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
ZrCl4-catalyzed nucleophilic dearomatization of 2-hydroxy-pyrimidines:
A concise synthesis of novel 3,4-dihydropyrimidin-2(1H)-ones
containing a phosphonic ester group
⇑
⇑
Kang-rui Li, Fan-jie Meng, Wen-feng Jiang , Lei Shi
State Key Laboratory of Fine Chemicals, School of Chemical Engineering, Dalian University of Technology, Dalian 116024, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Catalytic nucleophilic dearomatization of 2-hydroxypyrimidines with phosphites was effectively
achieved by utilizing ZrCl4 as the catalyst under mild conditions. This new methodology presents a direct
synthesis of 3,4-dihydropyrimidin-2(1H)-ones (DHPMs) from readily accessible 2-hydroxypyrimidine
derivatives. Various of mono-substituted, di-substituted and tri-substituted 2-hydroxypyrimidines
underwent a nucleophilic dearomatization to furnish a kind of novel phosphonic ester-containing
DHPMs unreported before in high yields.
Received 19 March 2021
Revised 27 April 2021
Accepted 29 April 2021
Available online 4 May 2021
Keywords:
Ó 2021 Elsevier Ltd. All rights reserved.
Nucleophilic Dearomatization
2-Hydroxy-pyrimidines
3,4-Dihydropyrimidin-2(1H)-one
Phosphites
3,4-Dihydropyrimidinones (DHPMs), one kind of perennially
popular N-heterocyclic compound in pharmaceutical chemistry
[1], exhibits a wide range of biological properties[2,3], such as anti-
cancer activity[4], calcium channel inhibition[5], anti-inflamma-
tory activity[6], antibacterial activity[7], etc. The preparation of
DHPMs always relies on three-component condensation of alde-
hyde, acetoacetate and urea, namely as the Biginelli reaction[8].
A great number of catalysts were developed to enable Biginelli con-
densation to occur effectively, even in an enantioselective manner
[9,10]. However, most of the successful examples are focused on
furnishing the 4-aryl or 4-alkyl substituted DHPMs owing to the
limited types of aldehydes used[11]. Considering the wide applica-
tions of such compounds in medicinal chemistry, the development
of innovative methods to synthesize various DHPMs, especially the
unreported DHPMs with heteroatom substituted at C4 position, is
of great significance for drug discovery.Scheme 1.
On the other hand, catalytic dearomatization offers a rapid and
unique methodology to transform two-dimensional aromatic to
complex three-dimensional cyclic molecules. The organic chem-
istry community has been enthusiastic about this synthetic con-
cept and some elegant strategies were reported to overcome the
high energy barrier of a dearomatization process[12,13]. The
known reports mainly include electron-rich polycyclic aromatics,
such as phenols[14], naphthol[15], indole[16], pyrrole[17], etc.
For those more stable aromatics, such as pyridines[18], quino-
lones[19] and isoquinolines[20], to be preactivated or activated
in situ by stoichmeric electrophiles followed by a direct addition
of nucleophile shows a tremendously effective dearomatization
strategy. These reactions include addition of arylboronic acids
[21], alkynes[22], aryl and alkyl zinc reagents[23], indoles[24],
and other nucleophiles[25,26] to pyridinium and quinolinium
salts. Despite the tremendous progress in this field, to the best of
our knowledge, the direct nucleophilic dearomatization of pyrim-
idines has still remained elusive to date.
In line with our continuing research interests in asymmetric
hydrogenation of N-heteroaromatics, we recently realized a transi-
tion-metal catalysed asymmetric hydrogenation of 2-hydrox-
ypyrimidines and an organocatalytic asymmetric transfer
hydrogenation of 2-hydroxypyrimidines, respectively, which rep-
resent an entirely new approach to synthesize chiral DHPMs.
[27,28] The key to success of this project is the hydroxyl-oxo tau-
tomerism of 2-hydroxypyrimidine causes certain loss of aromatic-
ity, which inspire us seek a possibility for a direct nucleophilic
dearomatization of 2-hydroxypyrimidine to give various DHPMs.
Herein, we will describe an effective direct nucleophilic dearoma-
tion of 2-hydroxypyrimidine with phosphites as nucleophiles in
the presence of a catalytic amount of ZrCl4, furnishing a novel
DHPMs containing a phosphonic ester group at C4 position.
At the outset, we chose 5-methyl-4-phenylpyrimidin-2-ol (1a)
as the model substrate to optimize the dearomatization reaction
⇑
Corresponding authors.
E-mail addresses: jiangwf@dlut.edu.cn (W.-f. Jiang), shileichem@dlut.edu.cn
(L. Shi).
https://doi.org/10.1016/j.tetlet.2021.153149
0040-4039/Ó 2021 Elsevier Ltd. All rights reserved.

K.-r. Li, F.-j. Meng, W.-f. Jiang et al.
Tetrahedron Letters 73 (2021) 153149
briefly tested common Lewis acids as catalysts (entries 4–9) and
found that the yield could be increased when using ZrCl4, which
gave the product 3a with higher yield than other acids (entry 9,
44% yield). Subsequently, several solvents were tested and indi-
cated the solvent had a critical impact on reactivity (entries 10–
16). When THF used as the solvent, the reactivity was significantly
improved and 2a was obtained nearly quantitative yield (98%) in a
shorter reaction time (entry 16). Finally, the optimized reaction
conditions were established as follows: 3 mol% ZrCl4 ,1.5 equiv of
dimethyl phosphites in THF at room temperature.
Having defined an optimal reaction protocol, we explored the
substrate scope to test the generality. The results are summarized
in Table 2. Firstly, this dearomatization reaction was able to be
smoothly conducted with varieties of phosphite esters (Table 2,
entries 1–3). Notably, a bulkier nucleophile 2c with isopropyl
group resulted in a slightly decreased yield but still 85%. But when
it came to phenyl group, the reaction did not occur at all (entry 4).
It is obvious that the increase of steric hindrance of ester group
decrease nucleophilicity of phosphorus. But when other phospho-
rus hydrogen reagents, diphenylphosphine oxide, were used, the
reaction still could proceed smoothly (Table 2, entries 5). Next, a
serious of mono- and di-substituted substrates were examined
under the standard condition. For 5-methyl-4-aryl pyrimidin-2-
ols, the phenyl rings bearing both electron-donating and elec-
tron-withdrawing groups were well tolerated and the correspond-
ing DHPMs 3 were generally obtained in good yields (entries 6–11).
Moreover, various of diaryl substituted pyrimidin-2-ols also
proved as suitable substrates for dearomatization even through
bigger aryl groups were introduced at C5 position (entries 12–
16). In addition, the dearomatization reaction of 4-methylpyrim-
idin-2-ol also occurred well and 81% isolated yield was obtained
(entry 17).
Scheme 1. Synthesis strategies of 3,4-dihydropyrimidin-2(1H)-ones.
conditions. Initial investigations focused on valuating the catalytic
efficiencies of various acids, which were conducted with 1.5 equiv.
of dimethyl phosphite as a nucleophile in DCM as the solvent at
room temperature. To our delight, the desired dearomatization
product 3a was isolated in 8% yield in the presence of 3 mol% AcOH
(Table 1, entry 1). Encouraged by this result, further variation with
other acids was performed. Stronger brønsted acid, such as TsOH
and (+/ꢀ)-CPA, seemed to facilitate better this nucleophilic addi-
tion, but yields still were unsatisfactory (entries 2, 3). We also
What’s more, tri-substituted 2-hydroxypyrimidine 4, more
challenging substrates that can form quaternary stereocenter, has
also been tested in our lab (scheme 2). Gratifyingly, dearomatiza-
tion of coumpound 4 proceeded effortlessly under the standard
conditions, providing the DHPM bearing a quaternary stereocenter
Table 1
Evaluation of Reaction Parametersa
Table 2
Substrate Scope of Hydroxypyrimidine.a
b
entry
cat.
solvent
yield%
Entry
1 (R1, R2)
2 (OR)
3 (yield%)b
1
AcOH
DCM
8
2
TsOH
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
CHCl3
MeCN
EtOAc
MeOH
Et2O
29
14
12
22
16
29
12
44
37
51
59
76
36
88
98
1
2
3
4
5
6
7
8
1a (Ph, Me)
1a (Ph, Me)
1a (Ph, Me)
1a (Ph, Me)
2a (OMe)
2b (OEt)
2c (OiPr)
2d(OPh)
3aa (98)
3ab (95)
3ac (85)
–
3c
4
(+/ꢀ)-CPA
La(OTf)2
Cu(OTf)2
FeSO4ꢁ7H2O
Co(NO3)2ꢁ6H2O
ZnBr2
ZrCl4
ZrCl4
ZrCl4
ZrCl4
5
6
7
8
1a (Ph, Me)
2e (Ph)
3ae (76)
3ba (99)
3ca (98)
3da (94)
3ea (95)
3fa (80)
3ga (96)
3 ha (94)
3ia (91)
3ja (89)
3 ka (85)
3la (90)
3mc (81)
1b (3-MeC6H4, Me)
1c (4-MeC6H4, Me)
1d (3-ClC6H4, Me)
1e (4-ClC6H4, Me)
1f (3-MeOC6H4, Me)
1 g (2,4-F2C6H3, Me)
1 h (Ph, Ph)
1i (3-MeC6H4, 3-MeC6H4)
1j (4-MeC6H4, 4-MeC6H4)
1 k (3-ClC6H4, 3-ClC6H4)
1 l (4-ClC6H4, 4-ClC6H4)
1 m (Me, H)
2a (OMe)
2a (OMe)
2a (OMe)
2a (OMe)
2a (OMe)
2a (OMe)
2a (OMe)
2a (OMe)
2a (OMe)
2a (OMe)
2a (OMe)
2c (OiPr)
9
10
11
12
13
14
15
16d
9
10
11
12
13
14
15
16
17
ZrCl4
ZrCl4
ZrCl4
ZrCl4
1,4-dioxane
THF
a
Reaction condition: 1a (0.2 mmol), 2a (0.3 mmol), cat. (0.006 mmol), solvent
(2 mL), 24 h, room temperature.
b
a
Isolated yields.
Reaction condition: 1 (0.5 mmol), 2 (0.75 mmol), ZrCl4 (0.015 mmol), THF
(2 mL), 24 h, room temperature.
c
5 mol% CPA. CPA:1,10-binaphthyl-2,20-diyl hydrogenphosphate.
d
b
8h.
Isolated yields.
2

K.-r. Li, F.-j. Meng, W.-f. Jiang et al.
Tetrahedron Letters 73 (2021) 153149
Acknowledgements
We are grateful for the financial support from the Natural
Science Foundation of China (21772195) and Dalian University of
Technology Fundamental Research Fund (DUT20RC5030).
Appendix A. Supplementary data
Scheme 2. Synthesis of 3,4-dihydropyrimidones with a quaternary stereocenter.
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2021.153149.
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at C4 position in 70% isolated yield. It is noteworthy that such
DHPM could not be prepared via tranditional Biginelli reaction.
To demonstrate the scalability of this method, the reaction
between 1a and 2a was performed on a 5.4 mmol scale. As illus-
trated in Scheme 3, this reaction delivered 3a in 83% yield
(1.334 g), while the dosage of ZrCl4 could be reduced to 0.1 mol%.
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phosphite ester as nucleophile, furnishing a kind of novel DHPMs
unreported before. This reaction proceeded effortlessly with easily
available catalyst and reagents under mild conditions, which
showed a good practicality. Besides, DHPMs contain a quaternary
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Declaration of Competing Interest
[27] G.S. Feng, M.W. Chen, L. Shi, Y.G. Zhou, Angew. Chem. Int. Ed. 57 (2018) 5853–
5857.
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4442.
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
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