Transition-metal-free lactamization of C(sp3)-H bonds with CO2: Facile generation of pyrido[1,2-: A] pyrimidin-4-ones

Article abstract of DOI:10.1039/c9gc03659h

A novel carbonylation of C(sp³)-H bonds in pyridylamines with one atmosphere of CO₂ is reported to synthesize important pyrimidinones in good yields. This transition-metal-free and redox-neutral process features the use of a nontoxic

Full text of DOI:10.1039/c9gc03659h

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Transition-metal-free lactamization of C(sp3)–H
bonds with CO2: facile generation of pyrido[1,2-a]
Cite this: Green Chem., 2020, 22, 28
pyrimidin-4-ones†
Zhen Zhang,*‡a Xiao-Yu Zhou,‡b Jin-Gui Wu,b Lei Songb and Da-Gang Yu
Received 24th October 2019,
Accepted 27th November 2019
b,c
*
DOI: 10.1039/c9gc03659h
rsc.li/greenchem
A
novel carbonylation of C(sp3)–H bonds in pyridylamines with CO2 was reported by Zhang and Lv,4p who realized the
with one atmosphere of CO2 is reported to synthesize important efficient generation of 4-hydroxy-2(1H)-quinolinones from
pyrimidinones in good yields. This transition-metal-free and o-acetamidoacetophenones, albeit under a high pressure of
redox-neutral process features the use of a nontoxic carbonyl CO2 (3 MPa). Herein, we report a novel carbonylation of
source, broad substrate scope, good functional group tolerance, C(sp3)–H bonds in pyridylamines with one atmosphere of CO2
facile scalability and easy product derivatization.
to synthesize important pyrimidinones under transition-metal-
free and redox-neutral conditions (Scheme 1B).
The development of green and sustainable strategies for
organic synthesis has received increasing attention. A green
and recyclable building block may play a key role in these strat-
egies. As an ideal C1 building block, CO2 is nontoxic, abun-
dant, and recyclable. Therefore, it is highly important to utilize
CO2 to synthesize high-value-added chemicals in a sustainable
way.1 Among the diverse organic transformations of CO2,2 the
carbonylation with CO2 to synthesize carbonyl-containing het-
erocycles has attracted increasing attention,3 replacing highly
toxic and user-unfriendly CO and phosgene. Recently, signifi-
cant progress has been achieved in the carbonylation of C–H
with CO2 due to its high atom- and step-economy.4
Importantly, as it bears carbon with a higher valence than that
of CO, CO2 can act ideally as the combination of CO and oxi-
dants (CO2 = CO + [O]), realizing such carbonylations under
redox-neutral reaction conditions and reducing the cost and
heavy metal residues.5 However, most of the research in this
field is focused on the carbonylation of C(sp2)–H bonds.4a–n In
contrast, there are only few examples of carbonylation of
C(sp3)–H bonds with CO2.4o–q Notably, to the best of our
knowledge, only one example of lactamization of C(sp3)–H
Pyrimidinones are important motifs in many drug mole-
cules and widely investigated in medicinal chemistry.6
Therefore, many groups have developed synthesis methods to
generate such a structure efficiently.7 It is worth noting that
Zeng and co-workers developed an elegant Pd-catalyzed lacta-
mization of ketoimines with CO (Scheme 1A), which displays
broad substrate scope and high step economy.8 However, the
use of toxic CO and stoichiometric Cu(OAc)2 as the oxidant
increases the risk for heavy metal residues and hampers its
applications in industry. With our continuous interest in the
sustainable organic synthesis with CO2,4b,9 we wondered
whether we could realize the efficient carbonylation of the
C(sp3)–H bonds in ketoimines with CO2 to obtain pyrimidi-
nones under redox-neutral conditions. Such a scenario faces
several challenges. First, the thermodynamic stability and
kinetic inertness of CO2 render it difficult to realize efficient
transformations, especially under low pressure. Second, the
dearomatization of pyridines would occur during the reaction,
which make such processes even more challenging (Fig. 1).
aKey laboratory of Coarse Cereal Processing of Ministry of Agriculture and Rural
Affairs, College of Pharmacy and Biological Engineering, Chengdu University,
Chendu 610106, P. R. China. E-mail: zhangzhen1@cdu.edu.cn
bKey Laboratory of Green Chemistry & Technology of Ministry of Education, College
of Chemistry, Sichuan University, Chengdu 610064, P. R. China.
E-mail: dgyu@scu.edu.cn
cBeijing National Laboratory for Molecular Sciences, Beijing 100190, P. R. China
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c9gc03659h
‡These authors contributed equally to this work.
Scheme 1 Carbonylation of the C–H bond.
28 | Green Chem., 2020, 22, 28–32
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cates that it might be an intermediate for this transformation
and the cyclization might not occur easily at lower tempera-
tures. Other solvents, such as DMA, DMSO, diglyme, and THF,
were also tested (Table 1, entries 15–19). However, no better
results were obtained, indicating the unique role of DMF for
this reaction. No desired product was obtained in the absence
of CO2, demonstrating its crucial role as a carbonylative source
(Table 1, entry 20).
With the optimal reaction conditions in hand, we began to
expand the substrate scope of N-(2-pyridyl) ketoimines 1
(Table 2). First, we examined the substrate bearing mono-sub-
stituents on the phenyl ring (1a–n). As shown in Scheme 2,
various functional groups, such as electron-donating groups
(EDGs, –OMe, –OCF3) and electron-withdrawing groups
Fig. 1 Selected examples of bioactive pyrimidinones.
With such challenges in mind, we began to investigate the (EWGs, –CF3, –Cl, –SO2Me) at the ortho (1c), meta (1d–e), and
reaction using N-(2-pyridyl) ketoimine 1a as the substrate para (1f–m) positions of the phenyl ring, did not affect the
under one atmosphere of CO2 (Table 1). To our delight, the reaction. However, a substrate bearing a strong EWG, such as
desired product 2a was obtained in 61% yield with lithium the nitro group (1n), at the para position showed low reactivity
t-butoxide as the base in DMF at 120 °C for 24 h (Table 1, and was not suitable for this reaction. Besides the mono-sub-
entry 1). Other bases, such as NaOtBu, KOtBu and Cs2CO3, stituents, the substrates bearing di- (1o) or tri-substituents (1p)
were also tested but gave lower yields (Table 1, entries 2–4). on the phenyl ring can also undergo this transformation to
When using NaOtBu or KOtBu as the base, the reaction system provide the desired products in good yields. To our delight, our
was very viscous and 1a was transformed to a byproduct (see protocol was also suitable for the alkyl-substituted N-(2-pyridyl)
the ESI† for details), both of which might cause a lower yield ketoimine substrate 1q, which has not been reported via Pd-cat-
of 2a. The screening of the amount of LiOtBu demonstrated alysis.8 Furthermore, substrates bearing substituents on the pyr-
that 4.5 equivalents was the best choice (Table 1, entries 5–10). idine ring were also investigated. Similarly, the substrate with
Similar to our previous reports,4b the desired product was not EDGs on the pyridine ring (1s and 1u) showed better reactivities
detected when 1 equivalent of LiOtBu was used, indicating than those with EWGs (1t) and electron-neutral groups (1r).
that LiOtBu not only acts as a base but also participates in the Notably, the product 2r shows significant bioactivity and acts as
formation of intermediates. Subsequently, we evaluated the an ERR-alpha inverse agonist.6c Besides the mono-substituted
reaction temperature and found that 130 °C gave the highest pyrimidinones, to our delight, we could also generate the di-
yield (Table 1, entries 9 and 11–14). Although 2a was generated substituted ones (2w and 2x) in good yields.
in very low yield at 80 °C, the carboxylative product could be
After developing this method, we further demonstrated its
detected obviously by ESI-MS (Table 1, entry 11), which indi- utility in organic synthesis. First, we conducted the gram-scale
Table 1 Optimization of reaction conditionsa
Entry
Base
x
T/°C
Yieldb (%)
Entry
Base
x
T/°C
Yieldb (%)
1
2
3
4
5
6
7
8
9
LiOtBu
NaOtBu
KOtBu
Cs2CO3
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
3
3
3
3
1
2
2.5
3.5
4
120
120
120
120
120
120
120
120
120
120
61
35
22
12
N.D.
35
56
63
74
77
11
12
13
14
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
4.5
4.5
4.5
4.5
4.5
4.5
4.5
4.5
4.5
4.5
80
110
130
140
130
130
130
130
130
130
<5
67
87 (86)
86
23
47
35
17
5
15c
16d
17e
18 f
19g
20h
10
4.5
0
a Reaction conditions: 1a (0.2 mmol), 1 atm of CO2, 2 mL of DMF, 24 h. b GC yields are given with dodecane as an internal standard and the iso-
lated yield is given in parentheses. c DMA (2 mL). d DMSO (2 mL). e Diglyme (2 mL). f THF (2 mL). g 1,4-Dioxane (2 mL). h Under the atmospheric
of N2 instead of CO2.
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Table 2 Substrate scope investigationa
reaction of 1a and obtained the target product 2a in 73% yield
(Scheme 2). Moreover, product 2a could be functionalized to give
both 3 and 4 in quantitative yields (Scheme 3A). These results
indicated the great potential application of this transformation in
organic synthesis. In addition to 2r, a quorum sensing inhibitor
5
6d could be rapidly accessed in good yield via the carbonylation
of 1v followed by demethylation (Scheme 3B).
To gain more insight into the lactamization reaction, we
did some mechanistic studies (Scheme 4). To confirm the car-
boxylate as the intermediate (Table 1, entry 11), we added CH3I
to quench the reaction which was performed at 80 °C. We
detected the formation of the corresponding methyl ester by
ESI-MS and obtained product 2a in a higher yield (27% GC
yield, Scheme 4A). In contrast, neither 2a nor the intermediate
Scheme 3 Derivatization reaction.
a Reaction conditions: 1 (0.2 mmol), LiOtBu (4.5 equiv.), 1 atm of CO2,
2 mL of DMF, 24 h, 130 °C. Isolated yields. b 30 h.
Scheme 2 Gram-scale reaction.
30 | Green Chem., 2020, 22, 28–32
Scheme 4 Mechanism studies.
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(2019YJ0669), the National Key Research and Development
Program of China (2018YFC1602101) and the Fundamental
Research Funds for the Central Universities for financial
support. We also thank the comprehensive training platform
of the Specialized Laboratory in the College of Chemistry at
Sichuan University for compound testing.
Notes and references
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Scheme 5 Proposed mechanism.
could be detected by ESI-MS in the control experiments under
N2 (Scheme 4B). Therefore, we speculate that both the carboxy-
late intermediate and the ester could undergo the cyclization
reaction to provide the desired product.
Based on the results and previous reports,7e,10 we proposed
the following possible pathway (Scheme 5). 1a underwent
deprotonation in the presence of the strong base LiOtBu to
form 1a-1, which can further react with CO2 to generate inter-
mediates 1a-2 and 1a-3. Under standard conditions, 1a-3
t
might react with BuO− to generate 1a-4, which further trans-
forms to 2a in the presence of a base. In addition, 1a-3 might
also transform to 1a-5, which undergoes a cyclization reaction
to provide the desired product 2a.
Conclusions
In summary, we have developed an efficient transition metal-
free and external oxidant-free strategy to generate valuable
pyrimidinones via the carbonylation of C(sp3)–H bonds with
an atmospheric pressure of CO2, which is the more environ-
ment-friendly carbonylation source. This protocol features
broad substrate scope, good functional group tolerance, facile
scalability and easy product derivatization, thus providing
potential application in organic synthesis and the pharma-
ceutical industry.
Conflicts of interest
There are no conflicts to declare.
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We thank the National Natural Science Foundation of China
(21822108, 21801025, and 21502124), the “973” Project from
the MOST of China (2015CB856600), the “1000-Youth Talents
Program”, Sichuan Science and Technology Program
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