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

Abstract

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 carbonyl source, broad substrate scope, good functional group tolerance, facile scalability and easy product derivatization.

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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 strategies. As an ideal C1 building block, CO₂ is nontoxic, abundant, 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 heterocycles has attracted increasing attention,³ replacing highly toxic and user-unfriendly CO and phosgene. Recently, significant 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 oxidants (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 with CO₂ was reported by Zhang and Lv,^4p who realized the efficient generation of 4-hydroxy-2(1H)-quinolinones from o-acetamidoacetophenones, albeit under a high pressure of CO₂ (3 MPa). Herein, we report a novel carbonylation of C(sp³)–H bonds in pyridylamines with one atmosphere of CO₂ to synthesize important pyrimidinones under transition-metal-free and redox-neutral conditions (Scheme 1B).

Scheme 1 Carbonylation of the C–H bond.

Pyrimidinones are important motifs in many drug molecules 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 lactamization 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 pyrimidinones 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).

Fig. 1 Selected examples of bioactive pyrimidinones.

With such challenges in mind, we began to investigate the reaction using N-(2-pyridyl) ketoimine 1a as the substrate under one atmosphere of CO₂ (Table 1). To our delight, the desired product 2a was obtained in 61% yield with lithium t-butoxide as the base in DMF at 120 °C for 24 h (Table 1, entry 1). Other bases, such as NaO^tBu, KO^tBu and Cs₂CO₃, were also tested but gave lower yields (Table 1, entries 2–4). When using NaO^tBu or KO^tBu as the base, the reaction system was very viscous and 1a was transformed to a byproduct (see the ESI† for details), both of which might cause a lower yield of 2a. The screening of the amount of LiO^tBu demonstrated that 4.5 equivalents was the best choice (Table 1, entries 5–10). Similar to our previous reports,^4b the desired product was not detected when 1 equivalent of LiO^tBu was used, indicating that LiO^tBu not only acts as a base but also participates in the formation of intermediates. Subsequently, we evaluated the reaction temperature and found that 130 °C gave the highest yield (Table 1, entries 9 and 11–14). Although 2a was generated in very low yield at 80 °C, the carboxylative product could be detected obviously by ESI-MS (Table 1, entry 11), which indicates that it might be an intermediate for this transformation and the cyclization might not occur easily at lower temperatures. 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).

Table 1 Optimization of reaction conditions^a

Entry	Base	x	T/°C	Yield^b (%)	Entry	Base	x	T/°C	Yield^b (%)
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 isolated 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.
1	LiO^tBu	3	120	61	11	LiO^tBu	4.5	80	<5
2	NaO^tBu	3	120	35	12	LiO^tBu	4.5	110	67
3	KO^tBu	3	120	22	13	LiO ^t Bu	4.5	130	87 (86)
4	Cs2CO3	3	120	12	14	LiO^tBu	4.5	140	86
5	LiO^tBu	1	120	N.D.	15^c	LiO^tBu	4.5	130	23
6	LiO^tBu	2	120	35	16^d	LiO^tBu	4.5	130	47
7	LiO^tBu	2.5	120	56	17^e	LiO^tBu	4.5	130	35
8	LiO^tBu	3.5	120	63	18^f	LiO^tBu	4.5	130	17
9	LiO^tBu	4	120	74	19^g	LiO^tBu	4.5	130	5
10	LiO^tBu	4.5	120	77	20^h	LiO^tBu	4.5	130	0

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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-substituents 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 (EWGs, –CF₃, –Cl, –SO₂Me) at the ortho (1c), meta (1d–e), and para (1f–m) positions of the phenyl ring, did not affect the reaction. However, a substrate bearing a strong EWG, such as the nitro group (1n), at the para position showed low reactivity and was not suitable for this reaction. Besides the mono-substituents, the substrates bearing di- (1o) or tri-substituents (1p) on the phenyl ring can also undergo this transformation to provide the desired products in good yields. To our delight, our protocol was also suitable for the alkyl-substituted N-(2-pyridyl) ketoimine substrate 1q, which has not been reported via Pd-catalysis.⁸ Furthermore, substrates bearing substituents on the pyridine ring were also investigated. Similarly, the substrate with EDGs on the pyridine ring (1s and 1u) showed better reactivities than those with EWGs (1t) and electron-neutral groups (1r). Notably, the product 2r shows significant bioactivity and acts as an ERR-alpha inverse agonist.^6c Besides the mono-substituted pyrimidinones, to our delight, we could also generate the di-substituted ones (2w and 2x) in good yields.

Scheme 2 Gram-scale reaction.

Table 2 Substrate scope investigation^a

a Reaction conditions: 1 (0.2 mmol), LiO^tBu (4.5 equiv.), 1 atm of CO₂, 2 mL of DMF, 24 h, 130 °C. Isolated yields. b 30 h.

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After developing this method, we further demonstrated its utility in organic synthesis. First, we conducted the gram-scale 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).

Scheme 3 Derivatization reaction.

To gain more insight into the lactamization reaction, we did some mechanistic studies (Scheme 4). To confirm the carboxylate 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 could be detected by ESI-MS in the control experiments under N₂ (Scheme 4B). Therefore, we speculate that both the carboxylate intermediate and the ester could undergo the cyclization reaction to provide the desired product.

Scheme 4 Mechanism studies.

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 LiO^tBu to form 1a-1, which can further react with CO₂ to generate intermediates 1a-2 and 1a-3. Under standard conditions, 1a-3 might react with ^tBuO⁻ to generate 1a-4, which further transforms 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.

Scheme 5 Proposed mechanism.

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 environment-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 pharmaceutical industry.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

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 (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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Footnotes

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c9gc03659h

‡ These authors contributed equally to this work.

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