NHC-Catalyzed Enantioselective [3 + 3] Annulation to Construct 5,6-Dihydropyrimidin-4-ones

Article abstract of DOI:10.1021/acs.orglett.0c02832

The unprecedented enantioselective NHC-catalyzed [3 + 3] annulation of α-bromoenals with amidines via a dual C-N bond formation is described. The protocol allows a rapid preparation of 5,6-dihydropyrimidinones in acceptable yields with good enantioselectivities.

Full text of DOI:10.1021/acs.orglett.0c02832

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Letter
NHC-Catalyzed Enantioselective [3 + 3] Annulation to Construct 5,6-
Dihydropyrimidin-4-ones
Di Meng,∇ Yangxi Xie,∇ Qiupeng Peng, and Jian Wang*
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ABSTRACT: The unprecedented enantioselective NHC-cata-
lyzed [3 + 3] annulation of α-bromoenals with amidines via a
dual C−N bond formation is described. The protocol allows a
rapid preparation of 5,6-dihydropyrimidinones in acceptable yields
with good enantioselectivities.
[3 + 3] annulation of α-bromoenals with N-substituted
olecules possessing a pyrimidinones scaffold are of great
1
2
Minterest in medicinal chemistry and industry for their amidines, affording a variety of functionalized chiral 5,6-
dihydropyrimidinones. (See Scheme 1.) Note that this
chemistry includes a significant dual C−N bond formation.20
Our study was started by examining the model reaction of α-
bromoenals 1a with protected amidines 2a under the initial
conditions of catalyst A, Na2CO3 as the base, and
tetrahydrofuran (THF) as the solvent (see Table 1). First,
unprotected amidine was tested and no desired product was
formed. A few protected amidines then were examined. The
benzyl protecting group gave better performance than Boc,
tosyl, and phenyl groups, resulting in 45% yield and 36%
enantiomeric excess (ee) (Table 1, entries 1−4). By switching
from catalyst A to catalyst B, ee was decreased dramatically,
which indicated the importance of the Mes substituent in the
catalyst (Table 1, entry 5). Second, taking into account the fact
that the amino-indane-based carbene catalyst C is a more rigid
structure, it only achieves 15% ee and a slightly higher yield
(49%) (Table 1, entry 6). To further understand the effect of
catalyst, triazoline D and E,21 which are based on a morpholine
scaffold, were tested. Pleasingly, ee was increased to 65%
(Table 1, entries 7 and 8). Subsequently, bases and solvents
were screened. Cs2CO3 and THF led to a higher yield (85%)
and ee (75%) than others (Table 1, entries 9−14). Meanwhile,
by adding KOtBu and HOtBu, the reaction rate was improved,
affording 91% yield and 77% ee (Table 1, entry 15). In the
absence of KOtBu or HOtBu, lower yields and ee were
identified (see the Supporting Information (SI)). An excellent
yield (96%) and a high ee (85%) were achieved by further
decreasing the reaction temperature to −20 °C (Table 1, entry
biological activities, such as antiviral, antitumor, and
antibacterial properties. For example, applycyanin A3a was
proven to have antitumor and antiproliferative activity; BACE-
1 inhibitors B3b and C3c exhibited potent inhibition of β-
secretase in the treatment of Alzheimer’s disease. For the
construction of chiral pyrimidinone cores, the most common
way to introduce chiral centers is through multicomponent
condensation or multistep synthesis.4 Therefore, seeking a new
and efficient method to rapid construct chiral pyrimidinones is
still in high demand.
In the past few decades, N-heterocyclic carbenes (NHCs)
were developed prominently.5 Especially, NHC organocatalysis
has received great attention for its efficiency in the
construction of six-membered heterocycles.6 To our knowl-
edge, catalytic [3 + 3] annulation was widely explored by
utilizing NHC-bounded α,β-unsaturated acylazolium with
several bisnucleophiles. In 2009, Lupton7 reported the
synthesis of dihydropyranones by the reaction of NHC-
bounded α,β-unsaturated acylazoliums with enolates. Other
elegant works for enantioselective construction of dihydropyr-
anones via similar strategies were independently presented by
the groups of Biju,8 Bode,9 Chi,10 Ma,11 Studer,12 Ye,13 You,14
and others. Later on, Bode and co-workers reported the
catalytic [3 + 3] annulation of stabilized enamines15a or N-
sulfonylimines15b as bisnucleophiles to react with α,β-
unsaturated acylazoliums. In 2013, the Chi group16 uncovered
a [3 + 3] annulation example of NHC-bounded α,β-
unsaturated acylazoliums with enamides. Enders17 utilized
simliar strategy to fuse various tricyclic dihydropyridinones.
More recently, Biju18 and Chi19 independently disclosed the
example of thioamides as bisnucleophiles to construct
thiazinones via [3 + 3] annulation. Despite these achievements,
the trial of amidines as bisnucleophiles with α,β-unsaturated
acylazoliums has not yet been reported in NHC organo-
catalysis. Herein, we report the unprecedented NHC-catalyzed
Received: August 24, 2020
https://dx.doi.org/10.1021/acs.orglett.0c02832
© XXXX American Chemical Society
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16). In the proton transfer phase, we postulated that the
influence of KOtBu and HOtBu on the reaction rate is
considered to be crucial. In fact, the role of KOtBu has been
discussed by the group of Glorius in the report of an
enantioseletive NHC-catalyzed Stetter reaction.22 In this case,
KOtBu is found to significantly reduce the transition states
more than the pathways without it, and HOtBu is considered
to have an impact in the proton transfer step. By further
lowering the catalytic amount to 10 mol % or 5 mol %, the
reaction can still afford high yield and maintain a good ee,
although it takes a longer time (Table 1, entries 17 and 18).
With the optimal condition in hand (Table 1, entry 17), we
turned our attention to expanding the substrate scope. A
variety of α-bromoenals were tested first (see Scheme 2).
Electron-rich or electron-withdrawing groups at the para-
position of the β-phenyl group led to high yields and good ee
(3b−3e). Substituents at the meta- or ortho-position were also
tolerated and afforded good to high yields and good ee (3f−
3h). Pleasingly, naphthyl- or benzodioxin-substituted α-
bromoenals also afforded high yields and good ee (3i−3k).
Substrates bearing heterocycle rings such as furan, benzofuran,
or thiophene resulted in lower yields but maintained good ee
(3l−3n). When the R substituent is an alkyl group, the
reaction is still occurred, but the yield and enantioselectivity
are only moderate (3o).
Scheme 1. NHC-Catalyzed [3 + 3] Annulation for the
Construction of 5,6-Dihydropyrimidinones
The scope of the amidines was investigated next (see
Scheme 3). Either electron-donating or electron-withdrawing
a
Table 1. Optimization of the Reaction Conditions
b
c
entry
PG
catalyst
base
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
K2CO3
KOtBu
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3/KOtBu
Cs2CO3/KOtBu
Cs2CO3/KOtBu
Cs2CO3/KOtBu
solvent
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
toluene
MeCN
CH2Cl2
THF
THF/HOtBu
THF/HOtBu
THF/HOtBu
yield (%)
enantiomeric excess, ee (%)
1
2
3
4
5
6
7
8
9
Boc
Ts
A
A
A
A
B
C
D
E
E
E
E
E
E
E
E
E
E
E
trace
trace
31
45
38
49
47
54
73
53
85
65
47
61
91
96
93
78
−
−
5
36
5
Ph
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
−15
47
65
60
71
75
67
55
33
77
85
85
84
10
11
12
13
14
d
15
de
,
16
17
18
de f
, ,
de g
, ,
a
Reaction conditions: 1a (0.15 mmol), 2a (0.1 mmol), catalyst (20 mol %), base (0.15 mmol), solvent (1.0 mL), room temperature, 4 Å MS (100
b
c
d
mg), 12 h. Isolated yield. As determined by chiral HPLC. With the addition of Cs2CO3 (1.0 equiv), KOtBu (0.3 equiv), HOtBu (0.1 mL), THF
(0.9 mL), 2.5 h. Conditions: −20 °C, 5 h. Catalyst E (10 mol %), 15 h. Catalyst E (5 mol %), 48 h.
e
f
g
B
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a
a
Scheme 2. Scope of α-Bromoenals
Scheme 3. Substrate Scope of Amidines
a
Reaction conditions: 1a (0.15 mmol), 2a (0.1 mmol), catalyst E (10
a
Reaction conditions: 1a (0.15 mmol), 2a (0.1 mmol), catalyst E (10
mol %), Cs2CO3 (1.0 equiv), KOtBu (0.3 equiv), HOtBu (0.1 mL),
and THF (0.9 mL), −20 °C, 4 Å MS (100 mg).
mol %), Cs2CO3 (1.0 equiv), KOtBu (0.3 equiv), HOtBu (0.1 mL),
and THF (0.9 mL), −20 °C, 4 Å MS (100 mg). Catalyst E (20
mol %), 48 h.
b
Scheme 4. Postulated Mechanism
groups at the para position of phenyl ring were both tolerated
(4a−4d). Bearing a methyl or fluorine at the meta position was
also compatible with the optimal reaction conditions (4e, 4f).
The 2-naphthyl group or heterocycles (e.g., pyridine, furan, or
thiophene) were compatible with the catalytic manner (4g−
4j). When the aryl group was replaced by an alkyl substituent,
92% ee could still be obtained, but only 58% yield was
achieved (4k). When the benzyl group was replaced by p-
methoxybenzyl (4l) or n-butyl substituent (4m), acceptable
yields and good enantioselectivities were still obtained.
Unfortunately, no desired product was achieved when the
N,N-diphenyl guanidine was employed as a substrate. The
absolute configuration of the 4d was determined by single-
crystal X-ray crystallography, and other products were assigned
by analogy (see the Supporting Information).
A postulated mechanism is illustrated in Scheme 4. The
reaction starts from the release of NHC from its precursor in
the presence of base. The addition of NHC to α-bromoenal 1a
forms homoenolate I, which then undergoes a tautomerization
and debromination to afford α,β-unsaturated acyl azolium
intermediate II. Intermediate II reacting with amidine 2a can
quickly convert to intermediate III after 1,4-addition. After the
intramolecular cycloaddition of intermediate III, intermediate
C
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Author Contributions
∇These authors contributed equally.
IV is formed. With the collapse of IV, product 3a is released
and the active catalyst is regenerated.
To demonstrate the practical utility of this protocol, a gram-
scale synthesis was conducted under the standard reaction
conditions (Scheme 5), and 3a was obtained without any loss
of yield and enantioselectivity (97%, 85% ee).
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Scheme 5. Gram-Scale Synthesis
We thank the National Natural Science Foundation of China
(Nos. 21871160, 21672121), the National “Thousand Plan”
Youth Program of China, the National “Ten Thousand Plan
(Leading Talents)” of China, the Innovation Promotion
Program of Ministry of Science & Technology (China),Tsing-
hua University, the Bayer Investigator Fellow Award, and the
Fellowship of Tsinghua-Peking Centre for Life Sciences (CLS)
for their generous financial support.
REFERENCES
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In summary, we have developed an unprecedented carbene-
catalyzed [3 + 3] annulation of α-bromoenals with amidines to
yield 5,6-dihydropyrimidin-4-ones with good enantiocontrol.
This new protocol provides a rapid assembly of optically active
5,6-dihydropyrimidin-4-ones from simple and readily available
starting materials under mild reaction conditions.
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■
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Accession Codes
CCDC 2024823 contains the supplementary crystallographic
data for this paper. These data can be obtained free of
chargeviawww.ccdc.cam.ac.uk/data_request/cif, or by
emailingdata_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: + 44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
Jian Wang − School of Biotechnology and Health Sciences,
Jiangmen International Healthcare Innovation Institute, Wuyi
University, Jiangmen 529020, China; School of Pharmaceutical
Sciences, Tsinghua University, Beijing 100084, China;
orcid.org/0000-0002-3298-6367; Email: wangjian2012@
tsinghua.edu.cn
Authors
Di Meng − School of Biotechnology and Health Sciences,
Jiangmen International Healthcare Innovation Institute, Wuyi
University, Jiangmen 529020, China; School of Chemical
Engineering and Light Industry, Guangdong University of
Technology,, Guangzhou 510006, China
Yangxi Xie − School of Pharmaceutical Sciences, Tsinghua
University, Beijing 100084, China
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E
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