Palladium-catalyzed direct alkenylation of 2-methyl-4H-pyrido[1,2-a]pyrimidin-4-ones using oxygen as the oxidant

Abstract

A direct C-3 alkenylation of 2-methyl-4H-pyrido[1,2-a]pyrimidin-4-ones through palladium-catalyzed C–H activation using oxygen as the terminal oxidant has been developed. This method provides an easy access to functionalized new 2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one derivatives.

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The Fujiwara–Moritani reaction via C–H bond cleavage has emerged as a powerful tool to construct C–C bonds in recent years.¹ This synthetic strategy employing Pd,² Ru,³ Rh,⁴ and Cu⁵ complexes has been widely used to prepare various organic materials, natural products and drugs. Despite these impressive advances, the large or stoichiometric amounts of oxidants such as copper(II) salts,⁶ silver(I) salts,⁷ or organic oxidants⁸ were still required and produced as waste. The current challenge is to use green and ecological oxidants such as molecular oxygen to fulfill the catalytic cycle. To the best of our knowledge, only few reports have used pure oxygen as an oxidant.⁹ In addition, the substrate scope has remained limited.

The 4H-pyrido[1,2-a]pyrimidin-4-one moiety is an important scaffold in biologically molecules, medicines, and functional materials.¹⁰ Risperidone with this structural unit was the mostly widely prescribed as atypical antipsychotic drug.¹¹ More recently, some 3-vinyl-4H-pyrido[1,2-a]pyrimidin-4-one compounds have been reported as efflux pump inhibitors in Pseudomonas aeruginosa.¹² The construction of 4H-pyrido[1,2-a]pyrimidin-4-one scaffold is usually employed acid-catalyzed condensation or thermal cyclization reaction.¹³ Meanwhile, Vilsmeyer, Wittig and Suzuki reactions have been used to construct C–C bonds for further derivatization.^12a–c,14 Despite many efforts in this area, the transition-metal-catalyzed C–H bond functionalization can provide a facile and atom-economical route for the construction of 4H-pyrido[1,2-a]pyrimidin-4-one compounds.¹⁵ Herein, we disclose an efficient C-3 alkenylation of 2-methyl-4H-pyrido[1,2-a]pyrimidin-4-ones with alkenes through palladium-catalyzed C–H activation using oxygen as the terminal oxidant (Fig. 1).

Fig. 1 Selected examples of biologically active 4H-pyrido[1,2-a]pyrimidin-4-ones.

Initially, we investigated the reaction of 2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one 1a and n-butyl acrylate 2a in the presence of Pd(OAc)₂ (10 mol%) and pure oxygen as terminal oxidant in DMF at 80 °C for 24 h. We are pleased to find the coupling product 3a in 23% yield (Table 1, entry 1). Notably, the alkenylation product 3a was formed with absolute regio- and stereoselectivity (C-3 and E-isomers). As reported in previous literatures,¹⁶ an additive source was required to facilitate the Pd-catalyzed direct alkenylation. After acid additives screening, PivOH could dramatically enhance the reaction efficiency, promoting the yield of 3a to 43% (Table 1, entries 2–4). The reason for enhanced reactivity may be that Pd–PivOH combination could lower the energy of aromatic C–H bond cleavage.^6,17 Next, the amount of PivOH was investigated, the yield of product 3a could be increased up to 80% when 5 equiv. of PivOH was used (Table 1, entries 5–7). The basic additives (K₂CO₃ and pyridine) hindered the alkenylation process (Table 1, entries 8–9). Several other solvents were investigated but all with inferior yields (Table 1, entries 10–15). Meanwhile, the yield was obviously decreased when air was used as oxidant instead of pure oxygen (Table 1, entries 16). The reaction occurred faster when O₂ bubbling instead of O₂ bag for 12 h, but almost the same results were obtained for 24 h (Table 1, entries 6 and 17). The same reaction proceeded less efficiently by using other palladium source such as PdCl₂, Pd(OH)₂ and PdCl₂(CH₃CN)₂ (Table 1, entries 18–20). When the reaction was conducted in the presence of other oxidants under air, product 3a was obtained in 62% (tert-butyl hydroperoxide), 43% (H₂O₂), and 0% (I₂ and CuI) yield, respectively (Table 1, entry 21).

Table 1 Optimization of the reaction conditions^a

Entry	Cat	Additive (equiv.)	Solvent	Yield^b (%)
a Reaction conditions: 2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one 1a (0.5 mmol), n-butyl acrylate 2a (1.0 mmol), catalyst (10 mol%), O2 (gas bag) and additive in 1 mL of solvent at 80 °C for 24 h.b GC yield.c 12 h.d Using air as an oxidant.e O2 bubbling.f Other oxidants were used under air (tert-butyl hydroperoxide, H2O2, I2 and CuI; 2 equiv.).
1	Pd(OAc)2	—	DMF	23
2	Pd(OAc)2	AcOH (1)	DMF	32
3	Pd(OAc)2	PivOH (1)	DMF	43
4	Pd(OAc)2	TFA (1)	DMF	12
5	Pd(OAc)2	PivOH (3)	DMF	65
6	Pd(OAc)2	PivOH (5)	DMF	(56)^c80
7	Pd(OAc)2	PivOH (8)	DMF	79
8	Pd(OAc)2	K2CO3	DMF	Trace
9	Pd(OAc)2	Pyridine	DMF	6
10	Pd(OAc)2	PivOH (5)	DCE	39
11	Pd(OAc)2	PivOH (5)	1,4-Dioxane	53
12	Pd(OAc)2	PivOH (5)	DMA	68
13	Pd(OAc)2	PivOH (5)	DMSO	45
14	Pd(OAc)2	PivOH (5)	Toluene	57
15	Pd(OAc)2	PivOH (5)	NMP	48
16^d	Pd(OAc)2	PivOH (5)	DMF	60
17^e	Pd(OAc)2	PivOH (5)	DMF	(63)^c79
18	PdCl2	PivOH (5)	DMF	41
19	Pd(OH)2	PivOH (5)	DMF	54
20	PdCl2(CH3CN)2	PivOH (5)	DMF	46
21^f	Pd(OAc)2	PivOH (5)	DMF	≤ 62

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With the optimal reaction condition in hand, we explored the scope of olefins 2 (Table 2). As expected, all olefins could react smoothly with substrate 1a to generate the desired products in moderate to good yields. Acrylate esters successfully coupled with 1a to give the corresponding products 3a–e in 63–79% yield. Meanwhile, we demonstrated that non-activated styrene derivatives could be employed for this alkenylation via C–H activation (3f–j). The desired product 3f was generated from the coupling reaction of 1a with styrene in 73% yield. Styrene containing electron-withdrawing fluoro or chloro group gave us the desired products 3i–j in slightly low yield. In addition, acrylamide was proved to be a good coupling partner and provided the corresponding product 3k in 83% yield.

Table 2 Scope of olefins^a

a All reaction were performed with 1a (0.5 mmol), 2 (1.0 mmol), Pd(OAc)₂ (10 mol%), PivOH (5 equiv.), O₂ (gas bag), in 1 mL of DMF at 80 °C for 24 h. Isolated yields.

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We next probed the scope of 2-methyl-4H-pyrido[1,2-a]pyrimidin-4-ones under the optimized conditions (Table 3). 2-Methyl-4H-pyrido[1,2-a]pyrimidin-4-ones possessing methyl, fluoro or chloro groups were smoothly reacted with n-butyl acrylate or styrene and provided C-3 alkenylation products 3l–u in moderate to good yields (59–75%). Among them, fluoro or chloro substituents on 2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one ring led to a lower yield (∼10%) than methyl substituent. Fluoro or chloro group as functional substituent was compatible with this coupling reaction, providing an opportunity for further functionalization.

Table 3 Scope of 2-methyl-4H-pyrido[1,2-a]pyrimidin-4-ones^a

a All reaction were performed with 1b–f (0.5 mmol), 2 (1.0 mmol), Pd(OAc)₂ (10 mol%), PivOH (5 equiv.), O₂ (gas bag), in 1 mL of DMF at 80 °C for 24 h. Isolated yields.

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Finally, a plausible mechanism for the direct C-3 alkenylation of 2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one is shown in Scheme 1. Pd(OAc)₂ is treated with PivOH to get active Pd(OPiv)₂, which is proposed to enable efficient C–H activation. The C-3-palladated intermediate A is formed by the electrophilic attack of Pd(OPiv)₂ to substrate 1a. Then, the species A smoothly inserts into the olefin 2 to give intermediate B, which undergoes a β-hydrogen elimination to provide the coupling product 3. The Pd(0) can be reoxidized by O₂ to complete the catalytic cycle.

Scheme 1 A plausible mechanism.

Conclusions

In conclusion, we have developed a general and simple protocol for the direct C-3 alkenylation of 2-methyl-4H-pyrido[1,2-a]pyrimidin-4-ones via C–H activation using a Pd(OAc)₂-O₂-PivOH system. The transformation can proceed well without metal or organic oxidants. This methodology will be attractive for the construction of new 2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one derivatives, which are of importance in medicinal chemistry.

Acknowledgements

The work was financially supported by the National Natural Science Foundation of China (21201043).

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: ¹H and ¹³C NMR spectra of compounds 3a–3u. See DOI: 10.1039/c5ra02932e

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