Controllable Synthesis of Trifluoromethyl- or gem-Difluorovinyl-containing Analogues of Neonicotinoids by the Reaction of α-(Trifluoromethyl)styrenes with 2-Nitroimino-imidazolidine

A simple and straightforward addition or defluorination of α-(trifluoromethyl)styrenes with 2-nitroimino-imidazolidine (2a), 2-(nitromethylene)imidazolidine (2b), 2-cyanoimino-thiazolidine (2c), and (E)-1-methyl-2-nitroguanidine (2d), in a controlled manner, was developed. The hydroamination of α-(trifluoromethyl)styrenes with 2a, 2b, 2c, and 2d was completed in the presence of DBN at room temperature within 0.5–6 h, affording structurally diverse β-trifluoromethyl-β-arylethyl analogues of neonicotinoids in moderate to good yields. The γ,γ-difluoro-β-arylallyl analogues of neonicotinoids were also successfully synthesized via defluorination of α-(trifluoromethyl)styrenes, with 2a and 2c using NaH as base at an elevated temperature together with a prolonged reaction time of 12 h. The method features simple reaction setup, mild reaction conditions, broad substrate scope, high functional group compatibility, and easy scalability.


Introduction
Neonicotinoid insecticides, which act as insect nicotinic acetylcholine receptor (nAChR) agonists, are one of the most important classes of insecticides, and are used for crop protection and veterinary pest control due to their supreme insecticidal ability, broad insecticidal spectrum, mammalian safety, and unique mode of action [1][2][3][4]. Since the first commercialized neonicotinoid insecticide, Imidacloprid (IMI), was launched in 1991 by Bayer CropScience, considerable efforts have been made on the development of novel neonicotinoid insecticides with high insecticidal activity and low toxicity to mammalians, and thus other first, second, and third generation neonicotinoids have subsequently been taken into the market (Figure 1) [5][6][7][8].
Based on the above-mentioned considerations, we envisaged that the modification of flexible linkage of neonicotinoid insecticide by the incorporation of fluorine-containing groups into neonicotinoid might be realized through the nucleophilic addition or defluorination reaction between α-(trifluoromethyl)styrenes and nitrogen-containing heteroalicycles or guanidine under controlled reaction conditions. In this paper, we developed a facile and practical method for the synthesis of trifluoromethyl or gem-difluorovinylcontaining neonicotinoid analogs via hydroamination or mono-defluorinative amination of α-(trifluoromethyl)styrenes with different nitrogen-containing heteroalicycles or guanidine, respectively, in a controlled manner under basic conditions (Scheme 2). Molecules 2023, 28, x FOR PEER REVIEW 3 of 15 Scheme 1. The reaction of α-(trifluoromethyl)styrenes with nitrogen nucleophiles under the different reaction conditions [37][38][39][40].
Based on the above-mentioned considerations, we envisaged that the modification of flexible linkage of neonicotinoid insecticide by the incorporation of fluorine-containing groups into neonicotinoid might be realized through the nucleophilic addition or defluorination reaction between α-(trifluoromethyl)styrenes and nitrogen-containing heteroalicycles or guanidine under controlled reaction conditions. In this paper, we developed a facile and practical method for the synthesis of trifluoromethyl or gem-difluorovinyl-containing neonicotinoid analogs via hydroamination or mono-defluorinative amination of α-(trifluoromethyl)styrenes with different nitrogen-containing heteroalicycles or guanidine, respectively, in a controlled manner under basic conditions (Scheme 2). Scheme 2. Amination of α-(trifluoromethyl)styrenes with nitrogen nucleophiles (this work).

Results and Discussion
We began our investigation using the reaction of 4-(3,3,3-trifluoroprop-1-en-2-yl)-1,1′-biphenyl 1a with 2-nitroimino-imidazolidine 2a as the model reaction to optimize the reaction conditions (Table 1). Generally, the product distribution of the amination was highly dependent on the base employed. Thus, our first effort focused on the influence of the base on the outcome of this reaction. A mixture of unidentified byproducts was observed when LiHMDS was used as base (entry 1). Other inorganic bases such as KOH, Cs2CO3, and KOtBu gave a mixture of addition product 3aa and defluorination 4aa (entries 2-4). Among various organic bases examined, only DBN was found to be the most acceptable base for this hydroamination, providing 3aa in 97% yield (entry 13). The competing defluorination reaction was suppressed completely and no defluorinative product 4aa was detected. When the base was changed from DBN to TMG, TBD, and DBU, the product yields of 3aa decreased significantly (entries [10][11][12]. Other organic bases such as Et3N, TMEDA, DIPEA, DMAP, and DABCO, all resulted in no reaction (entries 5-9). Scheme 1. The reaction of α-(trifluoromethyl)styrenes with nitrogen nucleophiles under the different reaction conditions [37][38][39][40]. Scheme 1. The reaction of α-(trifluoromethyl)styrenes with nitrogen nucleophiles under the different reaction conditions [37][38][39][40].
Based on the above-mentioned considerations, we envisaged that the modification of flexible linkage of neonicotinoid insecticide by the incorporation of fluorine-containing groups into neonicotinoid might be realized through the nucleophilic addition or defluorination reaction between α-(trifluoromethyl)styrenes and nitrogen-containing heteroalicycles or guanidine under controlled reaction conditions. In this paper, we developed a facile and practical method for the synthesis of trifluoromethyl or gem-difluorovinyl-containing neonicotinoid analogs via hydroamination or mono-defluorinative amination of α-(trifluoromethyl)styrenes with different nitrogen-containing heteroalicycles or guanidine, respectively, in a controlled manner under basic conditions (Scheme 2).

Results and Discussion
We began our investigation using the reaction of 4-(3,3,3-trifluoroprop-1-en-2-yl)-1,1′-biphenyl 1a with 2-nitroimino-imidazolidine 2a as the model reaction to optimize the reaction conditions (Table 1). Generally, the product distribution of the amination was highly dependent on the base employed. Thus, our first effort focused on the influence of the base on the outcome of this reaction. A mixture of unidentified byproducts was observed when LiHMDS was used as base (entry 1). Other inorganic bases such as KOH, Cs2CO3, and KOtBu gave a mixture of addition product 3aa and defluorination 4aa (entries 2-4). Among various organic bases examined, only DBN was found to be the most acceptable base for this hydroamination, providing 3aa in 97% yield (entry 13). The competing defluorination reaction was suppressed completely and no defluorinative product 4aa was detected. When the base was changed from DBN to TMG, TBD, and DBU, the product yields of 3aa decreased significantly (entries [10][11][12]. Other organic bases such as Et3N, TMEDA, DIPEA, DMAP, and DABCO, all resulted in no reaction (entries 5-9). Scheme 2. Amination of α-(trifluoromethyl)styrenes with nitrogen nucleophiles (this work).

Results and Discussion
We began our investigation using the reaction of 4-(3,3,3-trifluoroprop-1-en-2-yl)-1,1biphenyl 1a with 2-nitroimino-imidazolidine 2a as the model reaction to optimize the reaction conditions (Table 1). Generally, the product distribution of the amination was highly dependent on the base employed. Thus, our first effort focused on the influence of the base on the outcome of this reaction. A mixture of unidentified byproducts was observed when LiHMDS was used as base (entry 1). Other inorganic bases such as KOH, Cs 2 CO 3 , and KOtBu gave a mixture of addition product 3aa and defluorination 4aa (entries 2-4). Among various organic bases examined, only DBN was found to be the most acceptable base for this hydroamination, providing 3aa in 97% yield (entry 13). The competing defluorination reaction was suppressed completely and no defluorinative product 4aa was detected. When the base was changed from DBN to TMG, TBD, and DBU, the product yields of 3aa decreased significantly (entries [10][11][12]. Other organic bases such as Et 3 N, TMEDA, DIPEA, DMAP, and DABCO, all resulted in no reaction (entries 5-9).
Further screening of the solvents indicated that CH 3 CN, THF, and NMP could afford excellent yields of 3aa (entries 13, 18, and 19), whereas the use of other solvents, such as DMSO, CH 2 Cl 2 , and toluene, resulted in lower yields (entries [15][16][17]. When the polar protic solvent CH 3 OH was used as solvent, only a small amount of the desired product 3aa was formed (entry 14). To our delight, decreasing the amount of DBN from 3.0 to 2.5 equivalents would also provide 3aa in excellent yield (97%, entry 20). Further decreasing the amount of DBN led to significant decrease in the yield (82%, entry 21). In addition, when the reaction was performed at 25 • C using NaH as a base for 12 h, defluorinative amination product 4aa was produced in 30% yield, whereas hydroamination product 3aa was not detected (entry 22). It was pleasing to find that elevating the reaction temperature to 40 • C and 60 • C significantly improved the yield of 4aa, to 43% and 71%, respectively (entries 23 and 24).  Entry Base (equiv.) Solvent  Further screening of the solvents indicated that CH3CN, THF, and NMP could afford excellent yields of 3aa (entries 13, 18, and 19), whereas the use of other solvents, such as DMSO, CH2Cl2, and toluene, resulted in lower yields (entries [15][16][17]. When the polar protic solvent CH3OH was used as solvent, only a small amount of the desired product 3aa was formed (entry 14). To our delight, decreasing the amount of DBN from 3.0 to 2.5 equivalents would also provide 3aa in excellent yield (97%, entry 20). Further decreasing the amount of DBN led to significant decrease in the yield (82%, entry 21). In addition, when the reaction was performed at 25 °C using NaH as a base for 12 h, defluorinative amination product 4aa was produced in 30% yield, whereas hydroamination product 3aa was not detected (entry 22). It was pleasing to find that elevating the reaction temperature to 40 °C and 60 °C significantly improved the yield of 4aa, to 43% and 71%, respectively (entries 23 and 24).  With the optimized reaction conditions in hand (Table 1, entry 20), the substrate scope of this novel hydroamination was then investigated. As shown in Scheme 3, when a series of α-(trifluoromethyl)styrenes were treated with 2-nitroimino-imidazolidine 2a, the reactions proceeded smoothly to deliver the corresponding addition products in moderate to good yields. Generally, α-(trifluoromethyl)styrenes bearing electron-withdrawing groups on the phenyl ring are more favorable for this conversion than electron-donating groups (3ca versus 3fa). However, the α-(trifluoromethyl)styrene having a strong electron-donating group such as CH 3 O was found to be an unsuitable substrate, and only a trace amount of addition product was observed. The reactions exhibited excellent functional group compatibility, and a wide range of functional groups, such as trifluoromethyl, cyano, methylsulfonyl, chloro, methylthio, trifluoromethoxy, nitro, formyl, and ester were well tolerated under the reaction conditions, which may serve as useful reaction handles for further derivatization. The steric effect of an ortho-substituent had an obvious influence on the reaction efficiency. Compared to paraand meta-substituted styrenes, ortho-substituted substrates were unreactive and only small amounts of addition products were observed (3oa and 3pa). In addition, 4-(3,3,3-trifluoroprop-1-en-2-yl)-1,1 -biphenyl 1a and 2-(3,3,3trifluoroprop-1-en-2-yl)naphthalene 1r were found to be good substrates for the reaction. Importantly, heterocyclic substrates such as 2-(3,3,3-trifluoroprop-1-en-2-yl)thiophene 1s and 2-chloro-5-(3,3,3-trifluoroprop-1-en-2-yl)pyridine 1t were also suitable for this reaction to give the desired products 3sa and 3ta in 71% and 79% yields, respectively. It was worth noting that in most cases, 0.5 or 1.0 equivalents of DBN were enough to make the hydroamination reaction proceed efficiently, and good results were achieved. thylsulfonyl, chloro, methylthio, trifluoromethoxy, nitro, formyl, and ester were well tolerated under the reaction conditions, which may serve as useful reaction handles for further derivatization. The steric effect of an ortho-substituent had an obvious influence on the reaction efficiency. Compared to para-and meta-substituted styrenes, ortho-substituted substrates were unreactive and only small amounts of addition products were observed (3oa and 3pa). In addition, 4-(3,3,3-trifluoroprop-1-en-2-yl)-1,1′-biphenyl 1a and 2-(3,3,3trifluoroprop-1-en-2-yl)naphthalene 1r were found to be good substrates for the reaction. Importantly, heterocyclic substrates such as 2-(3,3,3-trifluoroprop-1-en-2-yl)thiophene 1s and 2-chloro-5-(3,3,3-trifluoroprop-1-en-2-yl)pyridine 1t were also suitable for this reaction to give the desired products 3sa and 3ta in 71% and 79% yields, respectively. It was worth noting that in most cases, 0.5 or 1.0 equivalents of DBN were enough to make the hydroamination reaction proceed efficiently, and good results were achieved. To further verify the scope of this novel hydroamination reaction, four nitrogen-containing heteroalicycles (2b, 2c, 2e, and 2f) and two guanidines (2d and 2g) were subjected to the addition reaction with α-(trifluoromethyl)styrenes (1c, 1e, and 1t) under the To further verify the scope of this novel hydroamination reaction, four nitrogencontaining heteroalicycles (2b, 2c, 2e, and 2f) and two guanidines (2d and 2g) were subjected to the addition reaction with α-(trifluoromethyl)styrenes (1c, 1e, and 1t) under the optimized reaction conditions (Scheme 4). Gratifyingly, without further optimization of the reaction conditions, the reactions of 2-(nitromethylene)imidazolidine 2b, 2-cyanoiminothiazolidine 2c, and (E)-1-methyl-2-nitroguanidine 2d with α-(trifluoromethyl)styrenes proceeded smoothly and provided corresponding products in moderate to good yields, despite the fact that those substrates are structurally different. However, 2-(nitromethylene) hexahydropyrimidine 2e, 3-methyl-4-nitroimino-tetrahydro-1,3,5-oxadiazine 2f, and 2cyanoguanidine 2g were poor substrates and failed to furnish the desired products. Therefore, the reaction conditions must be further investigated.
To prove the preparative usefulness of the developed methods, three scale-up reactions were performed. All reactions were conducted in 5.0 mmol scale. Without further optimization of reaction conditions, the hydroamination of α-(trifluoromethyl)styrenes 1t with 2a and 2c, and the defluorinative reaction of α-(trifluoromethyl)styrenes 1u with 2a, were easy to scale-up, however, the desired products were obtained in slightly lower yields (3ta, 3tc, and 4ua, Scheme 6).
To prove the preparative usefulness of the developed methods, three scale-up reactions were performed. All reactions were conducted in 5.0 mmol scale. Without further optimization of reaction conditions, the hydroamination of α-(trifluoromethyl)styrenes 1t with 2a and 2c, and the defluorinative reaction of α-(trifluoromethyl)styrenes 1u with 2a, were easy to scale-up, however, the desired products were obtained in slightly lower yields (3ta, 3tc, and 4ua, Scheme 6). Surprisingly, the reaction of 2-bromo-3,3,3-trifluoroprop-1-ene 5 with 2-nitroiminoimidazolidine 2a also proceeded smoothly, affording the addition product 6 in moderate yield (Scheme 7). Notably, the remaining bromo group in the product offers the opportunity for further downstream diversification. Surprisingly, the reaction of 2-bromo-3,3,3-trifluoroprop-1-ene 5 with 2-nitroiminoimidazolidine 2a also proceeded smoothly, affording the addition product 6 in moderate yield (Scheme 7). Notably, the remaining bromo group in the product offers the opportunity for further downstream diversification.
Reactions were stirred using Teflon-coated magnetic stir bars. Elevated temperatures were maintained using thermostat-controlled silicone oil baths. 1 H NMR and 13 C NMR spectra were recorded on a 400 spectrometer (400 MHz for 1 H and 100 MHz for 13 C, respectively) using TMS as an internal standard. The 19 F NMR spectra were obtained on a 600 spectrometer (564 MHz) with CF3COOH as an internal standard. CDCl3, DMSO-d6, or (CD3)2CO were used as the NMR solvents. Data for 1 H, 13 C, and 19 F NMR were recorded as follows: chemical shift (δ, ppm), multiplicity (s = singlet, d = doublet, t = triplet, m = multiplet, q = quartet, dd = double of doublet). Coupling constants are reported in hertz (Hz). High resolution mass spectra (HRMS) were recorded on the EI or ESI mode using a Scheme 7. Reaction of 2-bromo-3,3,3-trifluoroprop-1-ene with 2a.
Reactions were stirred using Teflon-coated magnetic stir bars. Elevated temperatures were maintained using thermostat-controlled silicone oil baths. 1 H NMR and 13 C NMR spectra were recorded on a 400 spectrometer (400 MHz for 1 H and 100 MHz for 13 C, respectively) using TMS as an internal standard. The 19 F NMR spectra were obtained on a 600 spectrometer (564 MHz) with CF 3 COOH as an internal standard. CDCl 3 , DMSOd 6 , or (CD 3 ) 2 CO were used as the NMR solvents. Data for 1 H, 13 C, and 19 F NMR were recorded as follows: chemical shift (δ, ppm), multiplicity (s = singlet, d = doublet, t = triplet, m = multiplet, q = quartet, dd = double of doublet). Coupling constants are reported in hertz (Hz). High resolution mass spectra (HRMS) were recorded on the EI or ESI mode using a TOF mass analyzer. The melting points were measured on an open capillary using EZ-Melt automated melting point apparatus and were not corrected. HPLC were recorded on a Shimadzu LC-20AT. Silica gel (300-400 mesh size) was used for column chromatography. TLC analysis of reaction mixtures was performed using silica gel plates.

General Procedure for the Synthesis of the Target Compounds 3aa-td
To a glass tube charged with a stirring bar were added DBN (0.5-2.5 equiv.), α-(trifluoromethyl)styrenes (1a-t, 1.0 mmol), nitrogen nucleophiles 2a-d (1.0 mmol, 1.0 equiv.), and CH 3 CN (3 mL). The reaction was stirred for 0.5-6 h under room temperature (monitored by TLC). After the completion of reaction, the reaction mixture was quenched with a saturated aqueous solution of NH 4 Cl (15 mL) and extracted with ethyl acetate (3 × 15 mL). The organic layer was separated and dried over Na 2 SO 4 , filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel using n-hexane/ethyl acetate (5/1-1/1) as eluent to afford the target compounds 3aa-td.

Conclusions
In summary, two novel series of fluorinated analogues of neonicotinoids were synthesized. The hydroamination and defluorinative amination of α-(trifluoromethyl)styrenes can be controlled by the subtle choice of reaction conditions and nitrogen nucleophiles. The hydroamination of α-(trifluoromethyl)styrenes with 2-nitroimino-imidazolidine (2a), 2-(nitromethylene)imidazolidine (2b), 2-cyanoimino-thiazolidine (2c), and (E)-1-methyl-2nitroguanidine (2d) proceeded efficiently in the presence of DBN and was completed at room temperature within 0.5-6 h, affording a number of structurally diverse β-trifluoromethylβ-arylethyl analogues of neonicotinoids in moderate to good yields. The γ,γ-difluoro-βarylallyl analogues of neonicotinoids were also successfully synthesized via defluorination of α-(trifluoromethyl)styrenes with 2-nitroimino-imidazolidine (2a) and 2-cyanoiminothiazolidine (2c) using NaH as base at an elevated temperature together with a prolonged reaction time of 12 h. The preliminary insecticidal activity tests indicated that only compounds 3ta, 3tc, and 3ca displayed moderate insecticidal activity against cowpea aphids (Aphis craccivora). The mortalities of 3ta, 3tc, and 3ca were 55%, 42%, and 38% at 250 mg/L, respectively. These preliminary results further demonstrated that flexible linkage such as the methylene group (-CH 2 -) in imidacloprid, plays a key role in the insecticidal activity. Increasing the length of carbon chain might be unfavorable for retaining insecticidal activity. The insecticidal evaluation of the target compounds against other insects such as armyworm and carmine spider, is underway in our laboratory.