Metal-Free Cascade Formation of C–C and C–N Bond for the Construction of 3-Cyano-2-Pyridones with Insecticidal Properties

A straightforward and efficient methodology has been developed for the synthesis of 3-cyano-2-pyridones via the C–C and C–N bond formation processes. A total of 51 diverse 3-cyano-2-pyridone derivatives were obtained in moderate to excellent yields. This reaction featured advantages such as a metal-free process, wide functional group tolerance, simple operation, and mild conditions. A plausible mechanism for the reaction was proposed. 3-cyano-2-pyridones as ricinine analogues for insecticidal properties were evaluated, and the compound 3ci (LC50 = 2.206 mg/mL) showed the best insecticidal property.


Optimization of the Reaction Conditions
In an initial effort, we began our investigation with the cascade cycloaddition of 1,3diphenylprop-2-yn-1-one 1aa and 2-cyano-N-methylacetamide 2aa in 1,4-dioxane in the presence of K 2 CO 3 as a base at 100 • C for 8 h (Table 1).To our delight, the preliminary result showed the desired product 3aa was obtained with an 81% yield (entry 1).The yield was decreased when the transition-metal-free reaction was conducted with Na 2 CO 3 or Cs 2 CO 3 instead of K 2 CO 3 (entries 2-3).Moreover, various kinds of bases were screened, whereas no reaction or trace transformation was observed, neither strong inorganic bases such as NaOH, NaH, EtONa, LiO t Bu, NaO t Bu, and KO t Bu (entries 4-9) nor organic bases including Et 3 N, DBU, and DABCO (entries 10-12) involving the transformation.Further investigation showed that this reaction was highly solvent-dependent (entries [13][14][15][16][17][18][19].When the reaction was carried out in DMSO, DMF, and NMP, an acceptable yield of 3aa was detected (entries 13-15).However, other solvents, such as CH 3 CN, toluene, THF, and EtOH, afforded only a trace amount of the desired product 3aa (entries [16][17][18][19].Finally, decreasing the amount of K 2 CO 3 lowered the yield (entry 20), while no obvious deviation was observed when the loading of K 2 CO 3 was increased (entries [21][22].On the basis of the above results, the optimal conditions for this transformation were obtained as follows: K 2 CO 3 (1.2equiv.) in 1,4-dioxane at 100 • C for 8 h.

Optimization of the Reaction Conditions
In an initial effort, we began our investigation with the cascade cycloaddit 1,3-diphenylprop-2-yn-1-one 1aa and 2-cyano-N-methylacetamide 2aa in 1,4-diox the presence of K2CO3 as a base at 100 °C for 8 h (Table 1).To our delight, the prelim result showed the desired product 3aa was obtained with an 81% yield (entry 1 yield was decreased when the transition-metal-free reaction was conducted with N or Cs2CO3 instead of K2CO3 (entries 2-3).Moreover, various kinds of bases were scr whereas no reaction or trace transformation was observed, neither strong inorganic such as NaOH, NaH, EtONa, LiO t Bu, NaO t Bu, and KO t Bu (entries 4-9) nor organic including Et3N, DBU, and DABCO (entries 10-12) involving the transformation.F investigation showed that this reaction was highly solvent-dependent (entries 1 When the reaction was carried out in DMSO, DMF, and NMP, an acceptable yield was detected (entries 13-15).However, other solvents, such as CH3CN, toluene, TH EtOH, afforded only a trace amount of the desired product 3aa (entries [16][17][18][19].F decreasing the amount of K2CO3 lowered the yield (entry 20), while no obvious dev was observed when the loading of K2CO3 was increased (entries [21][22].On the b the above results, the optimal conditions for this transformation were obtained lows: K2CO3 (1.2 equiv.) in 1,4-dioxane at 100 °C for 8 h.

Scope of the Reaction
With the optimum conditions in hand, the generality and scope of this metral-free cascade reaction of ynones and 2-cyanoacetamides were explored, and the results are shown in Table 2. Firstly, we studied the scope of alkynones with substituents in Ar-R 1 (entries 2-20).The reaction shows preference for electron-rich alkynones (Me, OMe) (entries 2-6), which provided the corresponding products in relatively higher yields than their counterparts bearing electron-withdrawing groups (F, Cl, Br, I, CF 3 ) (entries 7-20).Compared to the yield of 3ab and the yield of 3ad (87% vs. 73%), we found that the steric hindrance influenced this reaction.Particularly, a 2-naphthyl-substituted substrate could also be subjected to the reaction, and the corresponding product, 3au, was obtained with a 90% yield.Moreover, both alkyl-and heterocyclyl involving-alkynones were also suitable candidates for this transformation, and the corresponding products, 3av, 3aw, and 3ax were obtained in 83%, 76%, and 84% yields, respectively.

Gram-Scale of the Reaction
To demonstrate the reliability and practicality of this present synthetic protocol, a gram-scale preparation was performed using starting materials 1aa, where the desired product, 3aa, was isolated in an 83% yield (Scheme 1).

Gram-Scale of the Reaction
To demonstrate the reliability and practicality of this present synthetic protocol, a gram-scale preparation was performed using starting materials 1aa, where the desired product, 3aa, was isolated in an 83% yield (Scheme 1).Scheme 1. Gram-scale of 3aa.

Plausible Mechanism of the Reaction
On the basis of the aforementioned observations and previous reports [74], the mechanistic pathways of this cascade methodology were proposed and presented in Scheme

Study of the Insecticidal Properties of 3-Cyano-2-Pyridones
A literature survey implied that ricinine is well known as a compound with a high level of biological activity and has been proven valuable due to its insecticidal properties [77].Based on the structure of ricinine, we have prepared several 3-cyano-2-pyridones with novel scaffolds as ricinine analogues to evaluate their insecticidal activity (see the Scheme 1. Gram-scale of 3aa.

Plausible Mechanism of the Reaction
On the basis of the aforementioned observations and previous reports [74], the mechanistic pathways of this cascade methodology were proposed and presented in Scheme 2. Initially, 2-cyano-N-methylacetamide 2aa undergoes a K 2 CO 3 -initiated deprotonation of the CH 2 group to give carbanion A, and then the nucleophilic addition of carbanion A to the triple bond of ynone 1aa produces carbanion B. Subsequently, the carbanion B is quenched by a proton of the medium to generate intermediate C. Finally, an intramolecular cycloaddition of the intermediate C results in the formation of the cyclization product 3aa.

Gram-Scale of the Reaction
To demonstrate the reliability and practicality of this present synthetic protocol, a gram-scale preparation was performed using starting materials 1aa, where the desired product, 3aa, was isolated in an 83% yield (Scheme 1).Scheme 1. Gram-scale of 3aa.

Plausible Mechanism of the Reaction
On the basis of the aforementioned observations and previous reports [74], the mechanistic pathways of this cascade methodology were proposed and presented in Scheme

Study of the Insecticidal Properties of 3-Cyano-2-Pyridones
A literature survey implied that ricinine is well known as a compound with a high level of biological activity and has been proven valuable due to its insecticidal properties [77].Based on the structure of ricinine, we have prepared several 3-cyano-2-pyridones with novel scaffolds as ricinine analogues to evaluate their insecticidal activity (see the Scheme 2. Plausible mechanism.

Study of the Insecticidal Properties of 3-Cyano-2-Pyridones
A literature survey implied that ricinine is well known as a compound with a high level of biological activity and has been proven valuable due to its insecticidal properties [77].Based on the structure of ricinine, we have prepared several 3-cyano-2-pyridones with novel scaffolds as ricinine analogues to evaluate their insecticidal activity (see the experimental details in Supplementary Materials).Fortunately, in the trials of killing mealworm, we observed that the compounds 3au (LC 50 = 3.245 mg/mL) and 3bc (LC 50 = 3.579 mg/mL) exhibited powerful pesticidal activity using ricinine as a positive control.These results implied that 2-naphthyl and para-n-butyl benzene are good functional groups in the 3-cyano-2-pyridone framework as insecticides.Subsequently, the suitable functional candidate 3ci (LC 50 = 2.206 mg/mL) bearing 2-naphthyl and para-n-butyl benzene groups was obtained, and the insecticidal activity was evaluated.Upon comparing the LC 50 values in Figure 2, we found that the compound 3ci was the best candidate drug with insecticidal properties.
These results implied that 2-naphthyl and para-n-butyl benzene are good functional groups in the 3-cyano-2-pyridone framework as insecticides.Subsequently, the suitable functional candidate 3ci (LC50 = 2.206 mg/mL) bearing 2-naphthyl and para-n-butyl benzene groups was obtained, and the insecticidal activity was evaluated.Upon comparing the LC50 values in Figure 2, we found that the compound 3ci was the best candidate drug with insecticidal properties.

General Methods and Materials for the Synthesis of 3-Cyano-2-Pyridones 3
Unless otherwise stated, all reagents were used directly without further purification.Silica gel was purchased from Qing Dao Hai Yang Chemical Industry Co. (Qinqdao, China).All melting points were determined on a Beijing Science Instrument Dianguang Instrument Factory XT4B (Beijing, China) melting point apparatus and uncorrected. 1H and 13 C NMR spectra were measured on a 400 MHz JEOL JNM-ECZ400S/L1 spectrometer (Jeol Ltd., Tokyo, Japan), ( 1 H 400 MHz, 13 C 100 MHz), using CDCl3 as the solvent with tetramethylsilane (TMS) as the internal standard at room temperature.HRMS-ESI spectra were equipped with an ESI source and a TOF detector.PE is petroleum ether (60-90 °C).

General Methods and Materials for the Synthesis of 3-Cyano-2-Pyridones 3
Unless otherwise stated, all reagents were used directly without further purification.Silica gel was purchased from Qing Dao Hai Yang Chemical Industry Co. (Qinqdao, China).All melting points were determined on a Beijing Science Instrument Dianguang Instrument Factory XT4B (Beijing, China) melting point apparatus and uncorrected. 1H and 13 C NMR spectra were measured on a 400 MHz JEOL JNM-ECZ400S/L1 spectrometer (Jeol Ltd., Tokyo, Japan), ( 1 H 400 MHz, 13 C 100 MHz), using CDCl 3 as the solvent with tetramethylsilane (TMS) as the internal standard at room temperature.HRMS-ESI spectra were equipped with an ESI source and a TOF detector.PE is petroleum ether (60-90 • C).
A similar procedure was used for the preparation of products 3ab-3ck.

Table 1 .
Optimization of the reaction conditions a .

Table 1 .
Optimization of the reaction conditions a .
a Reaction conditions: the reactions were performed in a round-bottomed flask on a 0.6 mmol scale of 1, 0.5 mmol scale of 2 and 0.6 mmol scale of K 2 CO 3 in 1,4-dioxane (2 mL) at 100 • C for 8 h.b Isolated yields.