English

• 1.   Introduction

  4-Aminofuran-2(5H)-ones are of interest as the biologically active compounds and intermediates in the synthesis of natural products.^[1] For example, a novel insecticide flupyradifurone (Figure 1) with 4-aminofuran-2(5H)-one and pyridin-3-ylmethyl moieties was available in the market since 2014, and it showed excellent activity against several harmful pests without the severe honeybee toxicity associating with the other neonicotinoid insecticides.^[2] To the best of our knowledge, 5, 5-spirocyclicfuran-2(5H)-one moiety was found in lots of natural products and commercial agrichemicals, such as spirofrigilide, stypolactone, lambertellols A and B, yaoshanenolides A and B, as well as the commercial insecticides spirodiclofen and spiromesifen (Figure 1).^{[3, 4]} The 5-spirotetronic acid moiety in these molecules greatly improved the activities. However, the structure modification of flupyradifurone with 5-spirocyclic scaffold was not found in literature.^[5] In recent years, much more attention has been paid to the synthesis and biological activity evaluation of 5-spirotetramic and 5-spirotetronic acid derivatives.^[6] In the previous reports, we modified the structure of commercially available fungicide fenamidone with 5, 5-disubsitutedfuran-2(5H)-one scaffolds and found some novel lead compounds, which had excellent fungicidal activity against several phytopathogens.^[7] In order to find new lead compounds of insecticidal agents, the spirocycle or gem-dimethyl scaffolds were planned to be introduced into the molecule to replace two protons in the 5-position of flupyradifurone, and thus construct 4-((N-2, 2- difluoroethyl-N-pyridin-3-ylmethyl)amino)-5, 5-disubsitu-tedfuran-2(5H)-one for the insecticidal activity evaluation in our laboratory (Figure 1). When we carried out the substitution reaction with pyridin-3-ylmethyl chloride and 4-((2, 2-difluoroethyl)amino)-5, 5-disubsitutedfuran-2(5H)-one as preparation of the insecticide flupyradifurone, ^[2b] unexpected C(3)-alkylation products on 4-((2, 2-difluoro- ethyl)amino)-5, 5-disubsitutedfuran-2(5H)-one were obtai- ned in good to excellent yields (Scheme 1).^[8]

  Figure 1

  

  Figure 1.  Structures of typical 5, 5-spirocyclicfuran-2(5H)-one natural products and insecticides

  下载: 全尺寸图片 幻灯片

  Scheme 1

  

  Scheme 1.  Synthetic routes of 4-allyl, or 4-aminofuran-2(5H)- ones and Michael-addition of 4-alkyl-2-ynoate with amines

  下载: 全尺寸图片 幻灯片

  The synthetic strategy of our target molecule, 4-((N-2, 2- difluoroethyl-N-pyridin-3-ylmethyl)amino)-5, 5-disubsi-tutedfuran-2(5H)-one, should be changed. Recently, the Cu, Pd, Ru, Au-catalyzed syntheses of 3- or 4-substitutedfuran- 2(5H)-one by 4-hydroxyalkyl-2-ynoate with phenyl iodide, ketene, allylboronate, and phenylboronic acid were reported, and a chiral approach was also carried out (Scheme 1). But these strategies were not suitable for our desired targets.^[9] 4-(Pyridin-3-ylmethyl)-aminofuran-2(5H)-ones were also prepared by pyridin-3-ylmethyl amine with tetronic acid or 4-methoxyfuran-2(5H)-one in the presence of 4-toluene sulfonic acid or hydrochloric acid (Scheme 1), but this reaction does not work for our amines with strong electron-withdrawing groups.^[10] The nucleophilic Michael-additions of 4-alkyl-2-ynoate with primary or secondary alkyl, benzyl amines and anilines were preliminarily explored to synthesize enamine ester derivatives (Scheme 1).^[11] However the domino reaction of 4-hydroxyalkyl-2- ynoate and secondary heteroarylmethyl alkyl amines with strong electron-withdrawing groups (such as 2, 2-difluoro- ethyl, pyridin-3-ylmethyl, and pyrimidin-5-ylmethyl) was not disclosed in the references. In order to optimize the structure of insecticide flupyradifurone with 5, 5-germial dimethyl or 5, 5-spirocyclic and more heteroaryl methyl containing one more nitrogen atoms, herein, we explored the domino reaction of 4-hydroxyalkyl-2-ynoate and N-2, 2- difluoroethyl-N-heteroarylmethyl)amines (Scheme 2), andwould present the results.

  Scheme 2

  

  Scheme 2.  Domino reaction of N-2, 2-difluoroethyl-N-hetero- arylmethylamines with 4-hydroxyalkyl-2-ynoates

  下载: 全尺寸图片 幻灯片

  2.   Results and discussion

  After our endeavour to prepare target molecules in Scheme 2 using the methods in the reference ^[10] in the previous report was unsuccessful, ^[8] the domino reaction of N-(6-chloro-3-pyridylmethyl)-2, 2-difluoroethan-1-amine (1a) with 4-hydroxy-4-methyl-2-pentynoate (2a) was performed as a model, and the results are showed in Table 1. First, H₂O was used as solvent and the reaction was carried out at room temperature without or with ultrasound irradiation, the yields of 3a were 23% and 42%, respectively (Entries 1, 2). These results showed that ultrasound irradiation would assist the domino reaction, but the yield was not satisfactory. When Et₂O, tetrahydrofuran (THF), dichloro- methane (DCM), MeCN, H₂O and MeOH were utilized as solvents, the reactions were carried out at their reflux temperatures to afford 3a in 6%, 27%, 0, 10%, 60% and 78% yields (Entries 3~8), respectively. These results indicated that the solvent of water or alcohol should be suitable for this reaction in a short time, and alcohol was better than water. Then, EtOH, i-PrOH and n-BuOH were also tried at their reflux temperatures and gave 3a in 50%, 54% and 63% yields, respectively (Entries 9~11), while the reactions took place at reflux temperature of MeOH, the yields significantly decreased to 44%, 45% and 51% (Entresi 12~14), respectively. Although the yield was improved to 73% when H₂O was utilized as the solvent and reacted 48 h at reflux temperature (Entry 15), it was still lower than that of MeOH as solvent (Entry 8). So, MeOH should be the most suitable for this reaction at its reflux temperature. The increase of molar ratio of amine 1a to 2a from 1.0 to 1.5 and 2 resulted in little yield decrease under the same condition (Entries 16, 17) because of the side-reaction. When Na₂CO₃, NaHCO₃ and Et₃N were added to the reaction system, the yields also significantly decreased to 41%, 12% and 46%, respectively (Entries 18~20), which implied that the base did not assist this domino reaction. Therefore, the optimized condition for this domino reaction was n(2a):n(1a)＝1:1, MeOH as the solvent, 48 h at reflux temperature without catalyst and additives.

  Table 1

  

  Table 1.  Synthetic condition optimization of 3a

  下载: 导出CSV

  Entry	Solvent	n(2a):n(1a)	Additive	T/℃	t/h	Yielda/%
  1	H2O	1:1	—	25	96	23
  2	H2O	1:1	—	25	96	42b
  3	Et2O	1:1	—	30	96	6
  4	THF	1:1	—	66	96	27
  5	DCM	1:1	—	25	96	0
  6	MeCN	1:1	—	82	96	10
  7	H2O	1:1	—	100	96	60
  8	MeOH	1:1	—	65	48	78
  9	EtOH	1:1	—	78	48	50
  10	i-PrOH	1:1	—	97	48	54
  11	n-BuOH	1:1	—	117	48	63
  12	EtOH	1:1	—	65	48	44
  13	i-PrOH	1:1	—	65	48	45
  14	n-BuOH	1:1	—	65	48	51
  15	H2O	1:1	—	65	48	73
  16	MeOH	1:1.5	—	65	48	72
  17	MeOH	1:2	—	65	48	75
  18	MeOH	1:1	Na2CO3 (1 equiv.)	65	48	41
  19	MeOH	1:1	Na2CO3 (1 equiv.)	65	48	12
  20	MeOH	1:1	Na2CO3 (1 equiv.)	65	48	46
  a Reaction conditions: 1a (0.5 mmol), 2a (0.5 mmol) in 0.5 mL of solvents. b With ultrasound irradiation.

  Under the optimization condition, N-(3-pyridylmethyl)- 2, 2-difluoroethan-1-amines 1a~1f reacted with different 4-hydroxy-2-ynoates 2a~2d affording the products 3a~3x in 39%~83% isolated yields in a scale of 2 mmol starting materials (Table 2). The data in Table 2 showed that the yields of 5, 5-germial dimethyl products 3a~3f were higher than those of 5, 5-spirocyclic products 3g~3x because of the bulky hindrance of cyclohexane ring. In the other aspect, the yields of pyridylmethyl amines with F, Cl, Br and OCH₃ (1a~1d) were not significantly difference, while the yields of pyrimidylmethyl amines 1e and 1f were lower. This indicated that the strong electron-withdrawing effect decreases the yields. To further observe the reaction, N-benzyl-2, 2-difluoroethan-1-amine (1g), N-benzylmethyl- amine (1h), and N-(3-pyridyl-methyl)- methylamine (1i) were also utilized to the reaction with 4-hydroxy-4-methyl- 2-pentynoate (2a) (Table 3). The data in Table 3 clearly indicated that the products could be successfully obtained in 69%~85% yields. These results indicated that the reaction had a good compatible for amines and ynoates, and the fluorine atom did not significantly influence the reaction. In fact, the yield reached 88% when 10 mmol of 1a and 2a were used to repeat this domino reaction.

  Table 2

  

  Table 2.  Domino reaction of N-heteroarylmethyl-2, 2-difluoroethan-1-amines and 4-hydroxyalkyl-2-ynoates

  下载: 导出CSV

  Table 3

  

  Table 3.  Domino reaction of N-alkylarylmethylamine 1g~1i and 4-hydroxy-4-methyl-2-pentynoate (2a)

  下载: 导出CSV

  The structures of 3a~3x and 4a~4h were characterized with ¹H NMR, ¹³C NMR, and HR-ESI-MS data. Based on the above results and those in the literatures, ^[10~12] two possible mechanism (Scheme 3) for this domino reaction were proposed. Addition of methanol to 2a gave 5, then cyclization of 5 afforded 6, but the third step for amine addition to double bond of intermediate 6 and elimination of methanol did not work for these secondary amines (Scheme 3, Path A).^[10c] So the rational mechanism of this reaction should be the addition of amine to triple bond of 2a directly to afford intermediate 7, then cyclization of 7 lose an ethanol molecule and form 4-aminofuran-2(5H)-one (Scheme 3, Path B). After completed this work, the chloration of compound 3q with N-chlorosuccinimide in the presence of triethylamine at room temperature was carried out to afford the derivative 8. Its structure was unambiguously elucidated by ¹H NMR, ¹³C NMR, HR-ESI-MS data and the X-ray crystal diffraction (Figure 2). This result clearly showed that chlorine atom was located at C(3) position of 4-amino- furan-2(5H)-one, which further confirmed the structures of 3a~3x and 4a~4h.

  Scheme 3

  

  Scheme 3.  Proposed mechanism for the catalyst-free 4-aminofuran-2(5H)-one formation

  下载: 全尺寸图片 幻灯片

  Figure 2

  

  Figure 2.  Preparation and its crystal structure of compound 8

  下载: 全尺寸图片 幻灯片

  After completed these syntheses, the 5, 5-germial dimethyl and 5, 5-spirocyclic analogues of flupyradifurone were evaluated for their insecticidal activities against several harmful insects using protocol in previous report, ^[10d] and some of them exhibited excellent insecticidal activities (Table 4). Compounds 3a~3f had 50%~100% mortality against Mythimna seprata and Myzus persicae, but they did not show any mortality against Plutella xylostella and Tetranychus cinnabarinus, while compounds 3g~3x showed completely no activities against four target insects at the concentration of 600 µg•mL^－1. These results indicated that the 5, 5-germial dimethyl and 5, 5-spirocyclic modification of flupyradifurone did not significantly im prove its insecticidal activity compared with that of flupyradifurone. These bulky hindrance of 5, 5-spirocyclic group resulted in loss of insecticidal activity. For compounds 3a~3f, Cl, Br and F substitutitions in the pyridine were beneficial, OCH₃ substitutition and pyrimidine replacement resulted in decreasing of their insecticidal activities. Because of the importance of CH₂CHF₂ and pyridine ring for its activity in the flupyradifurone molecule, ^[2] the insecticidal activities of compounds 4a~4h with phenylmethyl and methyl against four target insects were not evaluated.

  Table 4

  

  Table 4.  Insecticidal activities (mortality/%) of compounds 3a~3x against several insects at 600 µg•mL^－1

  下载: 导出CSV

  Compd.	P. xylo-stella	M. sepa-rata	M. per-sicae	T. cinna-barinus
  3a	0	85	100	0
  3b	0	70	90	0
  3c	0	80	100	0
  3d	0	50	60	0
  3e	0	50	60	0
  3f	0	70	80	0
  3g	0	0	0	0
  3h	0	0	0	0
  3i	0	0	0	0
  3j	0	0	0	0
  3k	0	0	0	0
  3l	0	0	0	0
  3m	0	0	0	0
  3n	0	0	0	0
  3o	0	0	0	0
  3p	0	0	0	0
  3q	0	0	0	0
  3r	0	50	0	0
  3s	0	0	0	0
  3t	0	0	0	0
  3u	0	0	0	0
  3v	0	0	0	0
  3w	0	0	0	0
  3x	0	0	0	0
  8	0	0	0	0
  FPF	0	0	100	0

  3.   Conclusions

  A catalyst-free domino reaction of ethyl 4-hydroxyalkyl- 2-ynoate and N-heteroarylmethyl-N-2, 2-difluoroethan-1- amine was developed in MeOH under reflux temperature, which afforded 4-(N-(2, 2-difluoroethyl)(N-heteroaryl-me- thyl)amino)-5, 5-disubstitutedfuran-2(5H)-one in 39%~83% yields. Their structures were characterized by ¹H NMR, ¹³C NMR, HR-ESI-MS data and confirmed by the X-ray diffraction of compound 8. Compounds 3a and 3c exhibited 100% mortality against Myzus persicae at the concentration of 600 µg•mL^－1, respectively.

  4.   Experimental section

  4.1   General information

  Melting points (m.p.) were examined using a Yanagimoto apparatus without further corrected. ¹H NMR and ¹³C NMR spectra were recorded on a Bruker DPX 300 spectrometer with CDCl₃ as solvent and tetramethylsilane (TMS) as the internal standard. HR-ESI-MS data were acquired on a Linear Trap Quadropole (LTQ) Orbitrap instrument equipped with electrospray ionization source (ESI). Crystal structure was analyzed at an Thermo Fisher ESCALAB 250 X-ray diffractometry.

  All chemicals such as starting materials and reagents were purchased from commercial supplier (Energy Chemical) and used without further purification except as indicated. Organic solvents were concentrated under reduced pressure using a rotary evaporator or oil pump. All reactions were carried out using magnetic stirring. The silica gel chromatography was performed using 200~300 mesh flash silca gel (Qingdao Haiyang).

  4.2   Synthesis of compounds 3a~3x and 4a~4h

  N-Heteroaryl/arylmethyl-N-2, 2-difluoroethan-1-amine(1a~1i, 2 mmol) and ethyl 4-hydroxyalkyl-2-ynoate (2a~2d, 2 mmol) were dissolved in 2 mL of MeOH in a 10 mL tube with plug. The reaction mixture was heated to reflux temperature (65 ℃), stirred for 48 h, and cooled to room temperature. The solution was concentrated in vacuo, the crude products were purified by flash column chromatography on silica gel (200~300 mesh) and eluted with petroleum and ethyl acetate (V:V＝4:1 to 3:2) to afford compounds 3a~3x and 4a~4h.

  4-((N-2, 2-Difluoroethyl)(N-6-chloropyridin-3-ylmethyl)-amino)-5, 5-dimethylfuran-2(5H)-one (3a): White solid, 510 mg, yield 83%. m.p. 136~138 ℃; 1H NMR (300 MHz, DMSO-d₆) δ: 8.30 (d, J＝2.4 Hz, 1H), 7.70 (dd, J＝8.4, 2.4 Hz, 1H), 7.53 (d, J＝8.4 Hz, 1H), 6.29 (tt, ²J_FH＝54.7, J＝3.6 Hz, 1H), 4.79 (s, 1H), 4.68 (s, 2H), 3.83 (dt, ³J_FH＝14.5, J＝3.6 Hz, 2H), 1.54 (s, 6H); ¹³C NMR (75 MHz, DMSO-d₆) δ: 174.69, 170.63, 149.42, 148.56, 138.30, 131.92, 124.32, 114.57 (t, ¹J_CF＝240.7 Hz), 86.04, 81.98, 52.14 (t, ²J_FH＝25.0 Hz), 52.03, 25.61; HR-ESI-MS cacld for C₁₄H₁₆ClF₂N₂O₂ [M+H]⁺ 317.0863, found 317.0865.

  4-((N-2, 2-Difluoroethyl)(N-6-bromopyridin-3-ylmethyl)-amino)-5, 5-dimethylfuran-2(5H)-one (3b): White solid, 571 mg, yield 79%. m.p. 134~136 ℃; ¹H NMR (300 MHz, DMSO-d₆) δ: 8.28 (d, J＝2.4 Hz, 1H), 7.66 (d, J＝8.4 Hz, 1H), 7.59 (dd, J＝8.4, 2.4 Hz, 1H), 6.29 (tt, ²J_FH＝54.6, J＝3.6 Hz, 1H), 4.78 (s, 1H), 4.66 (s, 2H), 3.82 (dt, ³J_FH＝14.4, J＝3.6 Hz, 2H), 1.53 (s, 6H); ¹³C NMR (75 MHz, DMSO-d₆) δ: 174.68, 170.62, 149.13, 140.35, 138.08, 132.31, 128.07, 114.53 (t, ¹J_CF＝240.6 Hz), 86.05, 81.98, 52.14 (t, ²J_CF＝25.2 Hz), 52.06, 25.62; HR-ESI-MS cacld for C₁₄H₁₆BrF₂N₂O₂ [M+H]⁺ 361.0358, found 361.0355.

  4-((N-2, 2-Difluoroethyl)(N-6-fluoropyridin-3-ylmethyl)-amino)-5, 5-dimethylfuran-2(5H)-one (3c): White solid, 456 mg, yield 76%. m.p. 117~119 ℃; ¹H NMR (300 MHz, DMSO-d₆) δ: 8.13 (d, J＝2.7 Hz, 1H), 7.88~7.81 (m, 1H), 7.20 (dd, J＝8.4, 2.7 Hz, 1H), 6.29 (tt, ²J_FH＝55.0, J＝3.6 Hz, 1H), 4.80 (s, 1H), 4.68 (s, 2H), 3.82 (dt, ³J_FH＝14.7, J＝3.6 Hz, 2H), 1.54 (s, 6H); ¹³C NMR (75 MHz, DMSO-d₆) δ: 174.69, 170.67, 162.60 (¹J_FC＝234.1 Hz), 146.14 (³J_FC＝15.2 Hz), 140.80 (³J_FC＝8.1 Hz), 130.48, 114.58 (t, ¹J_CF＝240.8 Hz), 109.67 (²J_FC＝37.6 Hz), 85.95, 81.98, 52.00 (t, ²J_CF＝24.9 Hz), 51.88, 25.62; HR-ESI-MS calcd for C₁₄H₁₆F₃N₂O₂ [M+H]⁺ 301.1158, found: 301.1155.

  4-((N-2, 2-Difluoroethyl)(N-6-methoxypyridin-3-yl-methyl)amino)-5, 5-dimethylfuran-2(5H)-one (3d): White solid, 462 mg, yield 74%. m.p. 102~104 ℃; ¹H NMR (300 MHz, CDCl₃) δ: 8.01 (d, J＝2.1 Hz, 1H), 7.40 (dd, J＝8.4, 2.1 Hz, 1H), 6.79 (d, J＝8.4 Hz, 1H), 5.95 (tt, ²J_FH＝55.0, J＝3.6 Hz, 1H), 4.76 (s, 1H), 4.55 (s, 2H), 3.95 (s, 3H), 3.50 (dt, ³J_FH＝13.7, J＝3.6 Hz, 2H), 1.69 (s, 6H); ¹³C NMR (75 MHz, CDCl₃) δ: 174.08, 171.04, 164.03, 145.52, 137.11, 122.56, 112.89 (t, ¹J_CF＝243.2 Hz), 111.38, 85.86, 81.90, 53.26, 51.93, 51.16 (t, ²J_CF＝26.5 Hz), 25.73; HR-ESI-MS calcd for C₁₅H₁₉F₂N₂O₃ [M+H]⁺ 313.1358, found 313.1356.

  4-((N-2, 2-Difluoroethyl)(N-pyrimidin-5-ylmethyl)amino)- 5, 5-dimethylfuran-2(5H)-one (3e): White solid, 248 mg, yield 55%. m.p. 111~113 ℃; 1H NMR (300 MHz, CDCl₃) δ: 9.17 (s, 1H), 8.60 (s, 2H), 5.98 (tt, ²J_FH＝54.8, J＝3.6 Hz, 1H), 4.70 (s, 1H), 4.63 (s, 2H), 3.61 (dt, ³J_FH＝13.8, J＝3.6 Hz, 2H), 1.63 (s, 6H); ¹³C NMR (75 MHz, CDCl3) δ: 173.66, 170.56, 158.28, 155.26, 128.45, 112.96 (t, ¹J_CF＝243.3 Hz), 87.35, 81.94, 51.92 (t, ²J_CF＝25.5 Hz), 50.92, 25.69; HR-ESI-MS calcd for C₁₃H₁₆F₂N₃O₂ [M+H]⁺ 284.1205, found 284.1208.

  4-((2, 2-Difluoroethyl)(N-2-chloropyrimidin-5-ylmethyl)-amino)-5, 5-dimethylfuran-2(5H)-one (3f): White solid, 388 mg, yield 61%. m.p. 155~157 ℃; ¹H NMR (300 MHz, DMSO-d₆) δ: 8.65 (s, 2H), 6.30 (tt, ²J_FH＝54.8, J＝3.6 Hz, 1H), 4.83 (s, 1H), 4.69 (s, 2H), 3.89 (dt, ³J_FH＝14.8, J＝3.6 Hz, 2H), 1.54 (s, 6H); ¹³C NMR (75 MHz, DMSO-d₆) δ: 174.49, 170.54, 159.27, 159.05, 129.61, 114.62 (t, ¹J_CF＝240.6 Hz), 86.43, 82.01, 52.21 (t, ²J_CF＝24.9 Hz), 50.29, 25.57; HR-ESI-MS calcd for C₁₃H₁₅ClF₂N₃O₂ [M+H]⁺ 318.0815, found 318.0819.

  4-((N-2, 2-Difluoroethyl)(N-6-chloropyridin-3-ylmethyl)-amino)-5, 5-spirocyclohexylfuran-2(5H)-one (3g): White solid, 442 mg, yield 62%. m.p. 137~139 ℃; ¹H NMR (300 MHz, CDCl₃) δ: 8.25 (s, 1H), 7.49 (d, J＝8.4 Hz, 1H), 7.38 (d, J＝8.4 Hz, 1H), 5.97 (tt, ²J_FH＝55.0, J＝3.6 Hz, 1H), 4.76 (s, 1H), 4.67 (s, 2H), 3.57 (dt, ³J_FH＝13.7, J＝3.9 Hz, 2H), 1.84~1.19 (m, 10H); ¹³C NMR (75 MHz, CDCl₃) δ: 173.76, 170.97, 151.26, 147.95, 136.89, 129.56, 124.42, 112.92 (t, ¹J_CF＝243.3 Hz), 87.56, 84.04, 52.15, 52.03 (t, ²J_CF＝26.1 Hz), 33.98, 24.01, 21.66; HR-ESI-MS calcd for C₁₇H₂₀ClF₂N₂O₂ [M+H]⁺ cacld 357.1176, found 357.1172.

  4-((N-2, 2-Difluoroethyl)(N-6-bromopyridin-3-ylmethyl)-amino)-5, 5-spirocyclohexylfuran-2(5H)-one (3h): White solid, 501 mg, yield 63%. m.p. 113~115 ℃; ¹H NMR (300 MHz, CDCl₃) δ: 8.22 (d, J＝2.7 Hz, 1H), 7.53 (d, J＝8.1 Hz, 1H), 7.38 (dd, J＝8.4, 2.7 Hz, 1H), 5.97 (tt, ²J_FH＝55.0, J＝3.6 Hz, 1H), 4.76 (s, 1H), 4.64 (s, 2H), 3.57 (dt, ³J_FH＝13.7, J＝3.9 Hz, 2H), 1.80~1.15 (m, 10H); ¹³C NMR (75 MHz, CDCl₃) δ: 173.78, 171.06, 148.38, 141.76, 136.63, 130.00, 128.22, 112.91 (t, ¹J_CF＝243.2 Hz), 87.56, 84.08, 52.20, 52.05 (t, ²J_CF＝26.1 Hz), 33.97, 24.01, 21.66; HR-ESI-MS calcd for C₁₇H₂₀BrF₂N₂O₂ [M+H]⁺ cacld. 401.0671, found 401.0675.

  4-((N-2, 2-Difluoroethyl)(N-6-fluoropyridin-3-ylmethyl)-amino)-5, 5-spirocyclohexylfuran-2(5H)-one (3i): White solid, 434 mg, yield 64%. m.p. 102~104 ℃; ¹H NMR (300 MHz, CDCl₃) δ: 8.09 (s, 1H), 7.66~7.59 (m, 1H), 7. 00 (dd, J＝8.4, 3.0 Hz, 1H), 5.97 (tt, ¹J_FH＝55.1, J＝3.9 Hz, 1H), 4.78 (s, 1H), 4.68 (s, 2H), 3.56 (dt, ³J_FH＝13.6, J＝3.6 Hz, 2H), 1.85~1.15 (m, 10H); ¹³C NMR (75 MHz, CDCl₃) δ: 173.84, 171.12, 163.21 (d, ¹J_CF＝239.5 Hz), 146.10 (d, ³J_CF＝15.1 Hz), 139.44 (d, ³J_CF＝8.1 Hz), 128.24 (d, ⁴J_CF＝4.6 Hz), 112.91 (t, ¹J_CF＝243.3 Hz), 109.94 (d, ²J_CF＝37.5 Hz), 87.39, 84.10, 51.95, 51.83 (t, ²J_CF＝26.2 Hz), 33.98, 24.02, 21.67; HR-ESI-MS calcd for C₁₇H₂₀F₃N₂O₂ [M+ H]⁺ 341.1471, found 341.1476.

  4-((N-2, 2-Difluoroethyl)(N-6-methoxypyridin-3-yl-methyl)amino)-5, 5-spirocyclohexylfuran-2(5H)-one (3j): White solid, 429 mg, yield 61%. m.p. 108~110 ℃; 1H NMR (300 MHz, CDCl₃) δ: 8.01 (d, J＝2.4 Hz, 1H), 7.39 (dd, J＝8.4, 2.4 Hz, 1H), 6.80 (d, J＝8.4 Hz, 1H), 5.94 (tt, ²J_FH＝54.9, J＝3.9 Hz, 1H), 4.79 (s, 1H), 4.61 (s, 2H), 3.96 (s, 3H), 3.50 (dt, ³J_FH＝13.6, J＝3.9 Hz, 2H), 1.88~1.16 (m, 10H); ¹³C NMR (75 MHz, CDCl₃) δ: 173.99, 171.33, 164.03, 145.49, 137.05, 122.74, 112.86 (t, ¹J_CF＝243.2 Hz), 111.36, 86.59, 84.03, 53.26, 51.95, 51.47 (t, ²J_CF＝26.6 Hz), 33.97, 24.08, 21.69; HR-ESI-MS calcd for C₁₈H₂₃F₂N₂O₃ [M+H]⁺ 353.1671, found: 353.1676.

  4-((N-2, 2-Difluoroethyl)(N-pyrimidin-5-ylmethyl)-amino)-5, 5-spirocyclohexylfuran-2(5H)-one (3k): White solid, 314 mg, yield 48%. m.p. 157~158 ℃; ¹H NMR (300 MHz, CDCl₃) δ: 9.19 (s, 1H), 8.59 (s, 2H), 5.98 (tt, ²J_FH＝54.9, J＝3.6 Hz, 1H), 4.74 (s, 1H), 4.67 (s, 2H), 3.61 (dt, ³J_FH＝13.7, J＝3.6 Hz, 2H), 1.82~1.13 (m, 10H); ¹³C NMR (75 MHz, CDCl₃) δ: 173.51, 170.77, 158.37, 155.26, 128.54, 112.95 (t, ¹J_CF＝243.0 Hz), 88.19, 84.06, 52.11 (t, ²J_CF＝26.0 Hz), 50.98, 34.04, 24.03, 21.66; HR-ESI-MS calcd for C₁₆H₂₀F₂N₃O₂ [M+H]⁺ 324.1518, found 324.1516.

  4-((2, 2-Difluoroethyl)(N-2-chloropyrimidin-5-ylmethyl)-amino)-5, 5-spirocyclohexylfuran-2(5H)-one (3l): White solid, 385 mg, yield 54%. m.p. 155~157 ℃; ¹H NMR (300 MHz, CDCl₃) δ: 8.50 (s, 2H), 6.00 (tt, ²J_FH＝54.7, J＝3.6 Hz, 1H), 4.76 (s, 1H), 4.67 (s, 2H), 3.66 (dt, ³J_FH＝13.8, J＝3.6 Hz, 2H), 1.84~1.20 (m, 10H); ¹³C NMR (75 MHz, CDCl₃) δ: 173.37, 170.63, 161.18, 157.87, 127.24, 112.99 (t, ¹J_CF＝243.4 Hz), 88.68, 84.11, 52.13 (t, ²J_CF＝25.7 Hz), 50.56, 34.08, 24.02, 21.65; HR-ESI-MS calcd C₁₆H₁₉Cl- F₂N₃O₂ [M+H]⁺ 358.1128, found 358.1124.

  4-((2, 2-Difluoroethyl)(N-2-chloropyridin-5-ylmethyl)-amino)-5, 5-spiro(4-methoxycyclohexyl)furan-2(5H)-one (3m): White solid, 463 mg, yield 60%. m.p. 162~164 ℃; ¹H NMR (300 MHz, CDCl₃) δ: 8.24 (d, J＝2.4 Hz, 1H), 7.47 (dd, J＝8.4, 2.4 Hz, 1H), 7.38 (dd, J＝8.4, 0.9 Hz, 1H), 5.97 (tt, ¹J_FH＝55.0, J＝3.6 Hz, 1H), 4.79 (s, 1H), 4.63 (s, 2H), 3.56 (dt, ³J_FH＝13.8, J＝3.6 Hz, 2H), 3.34 (s, 3H), 3.17~3.06 (m, 1H), 2.08~1.79 (m, 8H); ¹³C NMR (75 MHz, CDCl₃) δ: 172.95, 170.63, 151.41, 147.91, 136.83, 129.36, 124.51, 112.79 (t, ¹J_CF＝241.8 Hz), 87.97, 82.95, 77.01, 55.38, 52.25, 52.08 (t, ²J_CF＝25.1 Hz), 32.72, 27.23. HR-ESI-MS calcd for C₁₈H₂₂ClF₂N₂O₃ [M+H]⁺ 387.1282, found 387.1284.

  4-((2, 2-Difluoroethyl)(N-2-bromopyridin-5-ylmethyl)-amino)-5, 5-spiro(4-methoxycyclohexyl)furan-2(5H)-one (3n): White solid, 524 mg, yield 61%. m.p. 155~157 ℃; ¹H NMR (300 MHz, CDCl₃) δ: 8.21 (d, J＝2.7 Hz, 1H), 7.54 (d, J＝8.4 Hz, 1H), 7.37 (dd, J＝8.4, 2.7 Hz, 1H), 5.97 (tt, ¹J_FH＝55.0, J＝3.6 Hz, 1H), 4.79 (s, 1H), 4.61 (s, 2H), 3.56 (dt, ³J_FH＝13.8, J＝3.6 Hz, 2H), 3.35 (s, 3H), 3.17~3.05 (m, 1H), 2.08~1.79 (m, 8H); ¹³C NMR (75 MHz, CDCl₃) δ: 172.94, 170.59, 148.35, 141.93, 136.53, 129.78, 128.29, 112.79 (t, ¹J_CF＝241.8 Hz), 88.00, 82.95, 77.00, 55.39, 52.31, 52.10 (t, ²J_CF＝25.0 Hz), 32.72, 27.24. HR-ESI-MS calcd for C₁₈H₂₂BrF₂N₂O₃ [M+H]⁺ 431.0776, found 431.0778.

  4-((2, 2-Difluoroethyl)(N-2-fluroropyridin-5-ylmethyl)-amino)-5, 5-spiro(4-methoxycyclohexyl)furan-2(5H)-one (3o): White solid, 454 mg, yield 62%. m.p. 119~121 ℃; ¹H NMR (300 MHz, CDCl₃) δ: 8.07 (d, J＝2.4 Hz, 1H), 7.64~7.60 (m, 1H), 7.00 (dd, J＝8.4, 3.0 Hz, 1H), 5.97 (tt, ¹J_FH＝55.2, J＝3.9 Hz, 1H), 4.80 (s, 1H), 4.64 (s, 2H), 3.56 (dt, ³J_FH＝13.8, J＝3.6 Hz, 2H), 3.35 (s, 3H), 3.18~3.06 (m, 1H), 2.08~1.80 (m, 8H); ¹³C NMR (75 MHz, CDCl₃) δ: 172.98, 170.65, 163.26 (d, ¹J_CF＝239.9 Hz), 146.05 (d, ³J_CF＝14.8 Hz), 139.39 (d, ³J_CF＝7.9 Hz), 128.07 (d, ⁴J_CF＝4.8 Hz), 112.81 (t, ¹J_CF＝243.2 Hz), 110.02 (d, ²J_CF＝37.7 Hz), 87.83, 82.95, 77.02, 55.37, 52.06, 51.89 (t, ²J_CF＝26.1 Hz), 32.72, 27.24; HR-ESI-MS calcd for C₁₈H₂₂F₃N₂O₃ [M+H]⁺ 371.1577, found 371.1574.

  4-((2, 2-Difluoroethyl)(N-2-methoxypyridin-5-ylmethyl)-amino)-5, 5-spiro(4-methoxycyclohexyl)furan-2(5H)-one (3p): White solid, 429 mg, yield 56%. m.p. 125~127 ℃; 1H NMR (300 MHz, CDCl₃) δ: 7.97 (d, J＝2.4 Hz, 1H), 7.36 (dd, J＝8.4, 2.4 Hz, 1H), 6.77 (d, J＝8.4 Hz, 1H), 5.93 (tt, ²J_FH＝54.9, J＝3.9 Hz, 1H), 4.78 (s, 1H), 4.56 (s, 2H), 3.92 (s, 3H), 3.48 (dt, ³J_FH＝13.8, J＝3.9 Hz, 2H), 3.33 (s, 3H), 3.18~3.05 (m, 1H), 2.06~1.78 (m, 8H); ¹³C NMR (75 MHz, CDCl₃) δ: 173.22, 170.94, 164.05, 145.42, 136.98, 122.57, 112.79 (t, ¹J_CF＝242.9 Hz), 111.39, 86.91, 82.91, 77.09, 55.34, 53.27, 52.07, 51.56 (t, ²J_CF＝26.7 Hz), 32.69, 27.26; HR-ESI-MS calcd for C₁₉H₂₅F₂N₂O₄ [M+ H]⁺ 383.1777, found 383.1779.

  4-((N-2, 2-Difluoroethyl)(N-pyrimidin-5-ylmethyl)-amino)-5, 5-spiro(4-methoxycyclohexyl)furan-2(5H)-one (3q): White solid, 346 mg, yield 49%. m.p. 117~119 ℃; ¹H NMR (300 MHz, CDCl₃) δ: 9.19 (s, 1H), 8.59 (s, 2H), 5.98 (tt, ²J_FH＝54.9, J＝3.6 Hz, 1H), 4.77 (s, 1H), 4.64 (s, 2H), 3.60 (dt, ³J_FH＝13.8, J＝3.6 Hz, 2H), 3.33 (s, 3H), 3.18~3.06 (m, 1H), 2.06~1.74 (m, 8H); ¹³C NMR (75 MHz, CDCl₃) δ: 172.72, 170.40, 158.42, 155.23, 128.39, 112.85 (t, ¹J_CF＝243.0 Hz), 88.63, 82.97, 55.41, 52.17 (t, ²J_CF＝26.0 Hz), 51.11, 32.76, 27.23. HR-ESI-MS calcd for C₁₇H₂₂F₂N₃O₃ [M+H]⁺ 354.1624, found 354.1619.

  4-((N-2, 2-Difluoroethyl)(N-2-chloropyrimidin-5-yl-methyl)amino)-5, 5-spiro(4-methoxycyclohexyl)furan-2(5H)-one (3r): White solid, 442 mg, yield 57%. m.p. 136~138 ℃; ¹H NMR (300 MHz, CDCl₃) δ: 8.48 (s, 2H), 5.99 (tt, ²J_FH＝54.8, J＝3.6 Hz, 1H), 4.76 (s, 1H), 4.63 (s, 2H), 3.64 (dt, ³J_FH＝13.9, J＝3.6 Hz, 2H), 3.34 (s, 3H), 3.18~3.05 (m, 1H), 2.08~1.76 (m, 8H); ¹³C NMR (75 MHz, CDCl₃) δ: 172.57, 170.25, 161.25, 157.84, 127.07, 112.89 (t, ¹J_CF＝243.6 Hz), 89.11, 83.02, 55.43, 52.18 (t, ²J_CF＝25.8 Hz), 50.71, 32.78, 27.22; HR-ESI-MS calcd for C₁₇H₂₁ClF₂N₃O₃ [M+H]⁺ 388.1234, found 388.1238.

  4-((N-2, 2-Difluoroethyl)(N-6-chloropyridin-3-ylmethyl)-amino)-5, 5-spiro(4-methoxyimino cyclohexyl)furan-2(5H)-one (3s): White solid, 422 mg, yield 53%. m.p. 173~175 ℃; ¹H NMR (300 MHz, CDCl₃) δ: 8.22 (d, J＝2.4 Hz, 1H), 7.46 (dd, J＝8.4, 2.4 Hz, 1H), 7. 37 (d, J＝8.4 Hz, 1H), 5.96 (tt, ¹J_FH＝54.8, J＝3.6 Hz, 1H), 4.82 (s, 1H), 4.61 (s, 2H), 3.82 (s, 3H), 3.55 (dt, ³J_FH＝13.7, J＝3.9 Hz, 2H), 3.34~3.28 (m, 1H), 2.70~1.97 (m, 7H); ¹³C NMR (75 MHz, CDCl₃) δ: 172.47, 170.34, 155.33, 151.46, 147.87, 136.82, 129.95, 124.49, 112.71 (t, ¹J_CF＝241.5 Hz), 87.90, 83.14, 60.90, 52.37, 52.03 (t, ²J_CF＝24.6 Hz), 34.12, 32.95, 27.37, 20.48; HR-ESI-MS calcd for C₁₈H₂₁ClF₂N₃O₃ [M+H]⁺ 400.1234, found 400.1238.

  4-((N-2, 2-Difluoroethyl)(N-6-bromopyridin-3-ylmethyl)-amino)-5, 5-spiro(4-methoxyimino cyclohexyl)furan-2(5H)-one (3t): White solid, 415 mg, yield 55%. m.p. 139~140 ℃; ¹H NMR (300 MHz, DMSO-d₆) δ: 8.21 (d, J＝2.4 Hz, 1H), 7.53 (d, J＝8.1 Hz, 1H), 7.35 (dd, J＝8.1, 2.4 Hz, 1H), 5.96 (tt, ¹J_FH＝55.0, J＝3.6 Hz, 1H), 4.83 (s, 1H), 4.59 (s, 2H), 3.82 (s, 3H), 3.55 (dt, ³J_FH＝13.7, J＝3.6 Hz, 2H), 3.34~3.27 (m, 1H), 2.68~1.96 (m, 7H); ¹³C NMR (75 MHz, DMSO-d₆) δ: 172.43, 170.32, 155.33, 148.31, 142.02, 136.52, 129.55, 128.29, 112.69 (t, ¹J_CF＝239.2 Hz), 87.96, 83.14, 60.91, 52.42, 52.05 (t, ²J_CF＝24.3 Hz), 34.15, 32.97, 27.38, 20.49; HR-ESI-MS calcd for C₁₈H₂₁BrF₂N₃O₃ [M+H]⁺ 444.0729, found 444.0726.

  4-((N-2, 2-Difluoroethyl)(N-6-fluoropyridin-3-ylmethyl)-amino)-5, 5-spiro(4-methoxyimino cyclohexyl)furan-2(5H)-one (3u): White solid, 421 mg, yield 47%. m.p. 79~80 ℃; ¹H NMR (300 MHz, DMSO-d₆) δ: 8.06 (d, J＝2.7 Hz, 1H), 7.63~7.57 (m, 1H), 7.01 (dd, J＝8.4, 3.0 Hz, 1H), 5.97 (tt, ¹J_FH＝55.0, J＝3.6 Hz, 1H), 4.84 (s, 1H), 4.62 (s, 2H), 3.83 (s, 3H), 3.54 (dt, ³J_FH＝13.8, J＝3.6 Hz, 2H), 3.34~3.26 (m, 1H), 2.68~1.98 (m, 7H); ¹³C NMR (75 MHz, CDCl₃) δ: 172.51, 170.40, 163.28 (¹J_CF＝239.9 Hz), 155.36, 146.04 (³J_FC＝14.9 Hz), 139.37 (³J_FC＝8.2 Hz), 127.84 (⁴J_FC＝4.8 Hz), 112.70 (t, ¹J_CF＝243.5 Hz), 110.05 (²J_FC＝37.8 Hz), 87.77, 83.16, 60.91, 52.18, 51.84 (t, ²J_CF＝26.0 Hz), 34.15, 32.98, 27.39, 20.49; HR-ESI-MS calcd for C₁₈H₂₁F₃N₃O₃ [M+H]⁺ 384.1530, found 384.1536.

  4-((N-2, 2-Difluoroethyl)(N-6-methoxypyridin-3-yl-methyl)amino)-5, 5-spiro(4-methoxyimino cyclohexyl)furan-2(5H)-one (3v): White solid, 464 mg, yield 59%. m.p. 122~124 ℃; ¹H NMR (300 MHz, CDCl₃) δ: 7.97 (d, J＝2.4 Hz, 1H), 7.35 (dd, J＝8.4, 2.4 Hz, 1H), 6.78 (d, J＝8.4 Hz, 1H), 5.92 (tt, ²J_FH＝54.9, J＝3.9 Hz, 1H), 4.84 (s, 1H), 4.53 (s, 2H), 3.94 (s, 3H), 3.85 (s, 3H), 3.48 (dt, ³J_FH＝13.8, J＝3.9 Hz, 2H), 3.34~3.28 (m, 1H), 2. 68~2.05 (m, 7H); ¹³C NMR (75 MHz, CDCl₃) δ: 172.69, 170.67, 164.10, 155.59, 145.42, 136.96, 122.32, 112.68 (t, ¹J_CF＝243.4 Hz), 111.46, 86.88, 83.11, 60.88, 53.30, 52.19, 51.52 (t, ²J_CF＝26.5 Hz), 34.14, 32.97, 27.42, 20.51; HR-ESI-MS calcd for C₁₉H₂₄F₂N₃O₄ [M+H]⁺ 396.1729, found 396.1725.

  4-((N-2, 2-Difluoroethyl)(N-pyrimidin-5-ylmethyl)-amino)-5, 5-spiro(4-methoxyiminocyclohexyl)furan-2(5H)- one (3w): White solid, 288 mg, yield 39%. m.p. 65~67 ℃; ¹H NMR (300 MHz, CDCl₃) δ: 9.19 (s, 1H), 8.58 (s, 2H), 5.97 (tt, ²J_FH＝55.0, J＝3.6 Hz, 1H), 4.82 (s, 1H), 3.79 (s, 3H), 3.59 (dt, ³J_FH＝13.8, J＝3.6 Hz, 2H), 3.34~3.05 (m, 1H), 2.70~2.06 (m, 7H); ¹³C NMR (75 MHz, CDCl₃) δ: 172.28, 170.21, 158.38, 155.21, 128.26, 112.75 (t, ¹J_CF＝243.2 Hz), 88.54, 83.19, 60.91, 52.13 (t, ²J_CF＝25.6 Hz), 51.20, 34.16, 32.98, 27.37, 20.49; HR-ESI-MS calcd for C₁₇H₂₁F₂N₄O₃ [M+H]⁺ 367.1546, found 367.1548.

  4-((N-2, 2-Difluoroethyl)(N-2-chloropyrimidin-5-yl-methyl)amino)-5, 5-spiro(4-methoxyiminocyclohexyl)furan-2(5H)-one (3x): White solid, 456 mg, yield 57%. m.p. 133~134 ℃; ¹H NMR (300 MHz, CDCl₃) δ: 8.47 (s, 2H), 5.98 (tt, ²J_FH＝54.9, J＝3.6 Hz, 1H), 4.81 (s, 1H), 4.61 (s, 2H), 3.80 (s, 3H), 3.66 (dt, ³J_FH＝13.8, J＝3.6 Hz, 2H), 3.34~3.06 (m, 1H), 2.69~1.95 (m, 7H); ¹³C NMR (75 MHz, CDCl₃) δ: 172.16, 170.09, 161.26, 157.83, 155.18, 126.94, 112.81 (t, ¹J_CF＝243.6 Hz), 89.01, 83.26, 60.93, 52.15 (t, ²J_CF＝25.8 Hz), 50.82, 34.19, 33.01, 27.37, 20.49; HR-ESI-MS calcd for C₁₇H₂₀ClF₂N₄O₃ [M+H]⁺ 401.1187, found 401.1185.

  4-N-Benzyl-N-2, 2-difluoroethylamino-5, 5-dimethyl-furan-2(5H)-one (4a): White solid, 421 mg, yield 75%. m.p. 89~90 ℃; 1H NMR (300 MHz, CDCl₃) δ: 7.43~7.31 (m, 3H), 7.18~7.14 (m, 2H), 5.93 (tt, ²J_FH＝55.2, J＝4.2 Hz, 1H), 4.75 (s, 1H), 4.62 (s, 2H), 3.50 (dt, ³J_FH＝13.7, J＝4.2 Hz, 2H), 1.66 (s, 6H); ¹³C NMR (75 MHz, CDCl₃) δ: 174.36, 171.27, 134.61, 128.92, 128.08, 126.49, 112.79 (t, ¹J_CF＝243.2 Hz), 85.28, 81.95, 54.62, 51.80 (t, ²J_CF＝26.9 Hz), 25.71; HR-ESI-MS calcd for C₁₅H₁₈F₂NO₂ [M+H]⁺ 282.1300, found 282.1304.

  4-N-(4-Methoxybenzyl)-N-2, 2-difluoroethylamino-5, 5-dimethylfuran-2(5H)-one (4b): Yellow solid, 464 mg, yield 75%. m.p. 132~134 ℃; ¹H NMR (300 MHz, CDCl₃) δ: 7.08 (d, J＝6.6 Hz, 2H), 6.91 (d, J＝6.6 Hz, 2H), 5.90 (tt, ²J_FH＝55.3, J＝4.2 Hz, 1H), 4.74 (s, 1H), 4.55 (s, 2H), 3.81 (s, 3H), 3.47 (dt, ³J_FH＝13.7, J＝4.2 Hz, 2H), 1.67 (s, 6H); ¹³C NMR (75 MHz, CDCl₃) δ: 174.32, 171.28, 159.36, 128.02, 126.28, 114.32, 112.85 (t, ¹J_CF＝242.9 Hz), 85.06, 81.92, 55.01, 54.06, 51.36 (t, ²J_CF＝26.8 Hz), 25.74; HR-ESI-MS calcd C₁₆H₂₀F₂NO₃ [M+H]⁺ 312.1406, found 312.1409.

  4-N-(4-Trifluoromethylbenzyl)-N-2, 2-difluoroethyl-amino-5, 5-dimethylfuran-2(5H)-one (4c): Yellow solid, 483 mg, yield 69%. m.p. 125~127 ℃; ¹H NMR (300 MHz, CDCl₃) δ: 7.66 (d, J＝7.8 Hz, 2H), 7.30 (d, J＝7.8 Hz, 2H), 5.97 (tt, ²J_FH＝55.1, J＝3.9 Hz, 1H), 4.74 (s, 1H), 4.69 (s, 2H), 3.55 (dt, ³J_FH＝13.7, J＝3.9 Hz, 2H), 1.65 (s, 6H); ¹³C NMR (75 MHz, CDCl₃) δ: 174.00, 170.82, 138.86, 130.42 (q, ²J_CF＝32.4 Hz), 126.66, 125.90 (q, ³J_CF＝3.6 Hz), 123.41 (q, ¹J_CF＝270.3 Hz), 112.79 (t, ¹J_CF＝243.0 Hz), 86.24, 81.86, 54.43, 52.06 (t, ²J_CF＝26.5 Hz), 25.70; HR-ESI-MS calcd for C₁₆H₁₇F₅NO₂ [M+H]⁺ 350.1174, found 350.1170.

  4-N-Benzyl-N-methylamino-5, 5-dimethylfuran-2(5H)-one (4d): White solid, 363 mg, yield 79%. m.p. 119~121 ℃; ¹H NMR (300 MHz, CDCl₃) δ: 7.41~7.29 (m, 3H), 7.18~7.14 (m, 2H), 4.60 (s, 1H), 4.49 (s, 2H), 2.94 (s, 3H), 1.65 (s, 6H); ¹³C NMR (75 MHz, CDCl₃) δ: 174.76, 172.08, 135.37, 128.69, 127.64, 126.31, 82.80, 81.58, 56.02, 38.45, 25.43; HR-ESI-MS calcd for C₁₄H₁₈NO₂ [M+H]⁺232.1332, found 232.1335.

  4-N-(4-Methoxybenzyl-N-methylamino-5, 5-dimethyl-furan-2(5H)-one (4e): Yellow liquid, 417 mg, yield 80%. ¹H NMR (300 MHz, CDCl₃) δ: 7.10 (d, J＝7.2 Hz, 2H), 6.90 (d, J＝7.2 Hz, 2H), 4.60 (s, 1H), 4.41 (s, 2H), 3.81 (s, 3H), 2.89 (s, 3H), 1.65 (s, 6H); ¹³C NMR (75 MHz, CDCl₃) δ: 174.72, 172.17, 159.04, 127.73, 127.20, 114.10, 82.59, 81.59, 55.45, 54.99, 38.08, 25.44; HR-ESI-MS calcd for C₁₅H₂₀NO₃ [M+H]⁺ 262.1438, found: 262.1434.

  4-N-(4-Trifluoromethylbenzyl-N-methylamino-5, 5-dimethylfuran-2(5H)-one (4f): Yellow liquid, 510 mg, yield 85%. ¹H NMR (300 MHz, CDCl₃) δ: 7.65 (d, J＝8.1 Hz, 2H), 7.30 (d, J＝8.1 Hz, 2H), 4.61 (s, 1H), 4.55 (s, 2H), 2.99 (s, 3H), 1.66 (s, 6H); ¹³C NMR (75 MHz, CDCl₃) δ: 174.57, 171.79, 139.54, 130.04 (q, ²J_CF＝32.6 Hz), 126.56, 125.72 (q, ³J_CF＝3.6 Hz), 123.51 (q, ¹J_CF＝270.5 Hz), 83.52, 81.58, 55.80, 38.65, 25.37; HR-ESI-MS calcd for C₁₅H₁₇F₃NO₂ [M+H]⁺ 300.1206, found 300.1207.

  4-N-(6-Chloropyridin-3-ylmethyl)-N-methylamino-5, 5-dimethylfuran-2(5H)-one (4g): White solid, 519 mg, yield 85%. m.p. 106~108 ℃; ¹H NMR (300 MHz, CDCl₃) δ: 8.24~8.21 (m, 1H), 7.51~7.47 (m, 1H), 7.36~7.33 (m, 1H), 4.58 (s, 1H), 4.46 (s, 2H), 2.98 (s, 3H), 1.62 (s, 6H); ¹³C NMR (75 MHz, CDCl₃) δ: 174.38, 171.57, 150.93, 147.89, 136.92, 130.02, 124.38, 83.76, 81.60, 53.36, 38.40, 25.30; HR-ESI-MS calcd for C₁₃H₁₆ClN₂O₂ [M+H]⁺267.0895, found 267.0898.

  4-N-(6-Methoxypyridin-3-ylmethyl)-N-methylamino-5, 5-dimethylfuran-2(5H)-one (4h): Yellow liquid, 421 mg, yield 80%. ¹H NMR (300 MHz, CDCl₃) δ: 7.95~7.93 (m, 1H), 7.39~7.34 (m, 1H), 7.73~7.69 (m, 1H), 4.54 (s, 1H), 4.35 (s, 2H), 3.86 (s, 3H), 2.88 (s, 3H), 1.59 (s, 6H); ¹³C NMR (75 MHz, CDCl₃) δ: 174.55, 171.91, 163.68, 145.11, 137.08, 123.41, 111.07, 82.87, 81.57, 53.30, 53.14, 37.95, 25.31. HR-ESI-MS calcd for C₁₄H₁₉N₂O₃ [M+H]⁺ 263.1390, found 263.1394.

  4.3   Synthesis of 3-chloro-4-((N-2, 2-difluoroethyl)(N-pyrimidin-5-ylmethyl)amino)-5, 5-spiro(4-methoxy-cyclohexyl)furan-2(5H)-one (8)

  To a solution of compound 3q (177 mg, 0.5 mmol) in acetonitrile (1 mL) were added N-chlorosuccinimide (67 mg, 0.5 mmol) and triethylamine (0.138 mL, 1 mmol) at room temperature. The resulting mixture was stirred overnight. After the reaction completion, the solvent was removed by rotary evaporator, and the residue was purified by silica gel flash column chromatography (200~300 mesh) and eluted with petroleum/ethyl acetate (V:V＝1:1) to afford 173 mg of compound 8 as a white solid, yield 89%. m.p. 165~167 ℃; ¹H NMR (300 MHz, CDCl₃) δ: 9.23 (s, 1H), 8.65 (s, 2H), 5.98 (tt, ²J_FH＝54.8, 3.6 Hz, 1H), 4.83 (s, 2H), 3.87 (td, ³J_FH＝14.1, 3.6 Hz, 2H), 3.33 (s, 3H), 3.19~3.13 (m, 1H), 2.09~1.71(m, 8H); ¹³C NMR (75 MHz, CDCl₃) δ: 166.40, 163.23, 158.56, 155.50, 129.23, 113.76 (t, ¹J_CF＝243.5 Hz), 95.22, 83.59, 55.46, 51.49, 51.44 (t, ²J_CF＝25.2 Hz), 33.25, 27.09; HR-ESI-MS calcd for C₁₇H₂₁ClF₂N₃O₃ [M+H]⁺ 388.1234, found 388.1236.

  4.4   X-ray diffraction analysis of compound 8

  The crystal of 8 was obtained from n-hexane/methanol (V:V＝1:20) solution. Its structure parameters were shown as following: crystal size 0.40 mm×0.35 mm× 0.33 mm, formula C₁₇H₂₀ClF₂N₃O₃, M＝387.81, monoclinic, a＝1.30969(3) nm, b＝0.792737(18) nm, c＝ 1.68448(4) nm, β＝100.038(2)°, V＝1.722137(7) nm³, ρ＝ 1.496 mg/mm³, space group P21/n, Z＝4, μ(Mo Kα)＝ 0.266 mm^－1, F(000)＝808, S＝1.037. Totally 14382 reflections were measured at T＝108.40 K, 3370 unique reflections (R_int＝0.0332) were used for all calculations and structure refinement. The final R₁＝0.0371, wR₂＝0.0759 (all data). The crystallographic data of 8 have been deposited with the Cambridge Crystallographic Data Centre (CCDC) with the accession number of 1860431. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_ request/cif.

  Supporting Information ¹H NMR, ¹³C NMR of 3a~3x and 4a~4h, and X-ray diffraction data of 8. The Supporting Information is available free of charge via the Internet at http://sioc-journal.cn.

  
  
• 1. [1]

     (a) Rao, Y. S. Chem. Rev. 1976, 76, 625.
     (b) Allan, R. D.; Johnston, G. A. R.; Kazlauskas, R.; Tran, H. W. J. Chem. Soc., Perkin Trans. 1 1983, 2983.
     (c) Gelmi, M. L.; Clerici, F.; Melis, A. Tetrahedron 1997, 53, 1843.
     (d) Li, J.; Yang, P.; Yao, M.; Deng, J.; Li, A. J. Am. Chem. Soc. 2014, 136, 16477.

  2. [2]

     (a) Nauen, R.; Jeschke, P.; Velten, R.; Beck, M. E.; Ebbinghaus-kintscher, U.; Thielert, W.; Wolfel, K.; Hass, M.; Kunz, K.; Raupach, G. Pest Manage. Sci. 2015, 71, 850.
     (b) Jeanmart, S.; Edmunds, A. J. F.; Lamberth, C.; Pouliot, M. Bioorg. Med. Chem. 2016, 24, 317.
     (c) Chen, X. D.; Seo, M.; Stelinski, L. L. Crop Prot. 2017, 98, 102.
     (d) Roditakis, E.; Stavrakaki, M.; Grispou, M.; Achimastou, A.; Waetermeulen, X. V.; Nauen, R.; Tsagkarakou, A. Pest Manage. Sci. 2017, 73, 1574.

  3. [3]

     (a) Murakami, T.; Morikawa, Y.; Hashimoto, M.; Okuno, T.; Harada, Y. Org. Lett. 2004, 6, 157.
     (b) Nomiya, M.; Murakami, T.; Takada, N.; Okuno, T.; Harada, Y.; Hashimoto, M. J. Org. Chem. 2008, 73, 5039.
     (c) Lachia, M. D.; Demesaeker, A.; Wolf, H. C.; Jung, P. J. M. WO 2012080115, 2012.
     (d) Liu, M.; Lin, S.; Gan, M.; Chen, M.; Li, L.; Wang, S.; Zi, J. Org. Lett. 2012, 14, 1004.

  4. [4]

     (a) Liu, T.-X. Crop Prot. 2004, 23, 505.
     (b) Nauen, R.; Bretschneider, T.; Elbert, A.; Fischer, R.; Tiemann, R. Pestc. Outlook 2003, 243.

  5. [5]

     (a) Jeschke, P.; Nauen, R.; Gutbrot, O.; Beck, M. E.; Matthiesen, S.; Hass, M.; Velten, R. Pestic. Biochem. Physiol. 2015, 121, 31.
     (b) Fan, Z. J.; Zong, G. N.; Ma, L. Y.; Chen, L.; Guo, X. F. CN 105503708, 2016.
     (c) Tian, P. Y.; Liu, D. Y.; Liu, Z. J.; Shi, J.; He, W. J.; Qi, P. Y.; Chen, J. X.; Song, B. A. Pest Manage. Sci. 2019, 75, 427.

  6. [6]

     (a) Fischer, R.; Himmler, T.; Nauen, R.; Reckmann, U.; Schmitt, W. In Proceedings of the International Plant Protection Congress, International Plant Protection Congress, Glasgow, 2007, pp. 100~103.
     (b) Zhao, J. H.; Ji, M. H.; Xu, X. H.; Cheng, J. L.; Zhu, G. N. Chin. Chem. Lett. 2009, 20, 1307.
     (c) Song, F. J.; Liu, Y. H. J. Organomet. Chem. 2014, 694, 502.
     (d) Melikyan, G. S.; Hovhannisyan, A. A.; Hayotsyan, S. S. Synth. Commun. 2012, 42, 2267.
     (e) Muehlebach, M.; Boeger, M.; Cederbaum, F.; Cornes, D.; Friedmann, A. A.; Glock, J.; Niderman, T.; Stoller, A.; Wagner, T. Bioorg. Med. Chem. 2009, 17, 4241.
     (f) Liu, Z. H.; Lei, Q.; Li, Y. Q.; Xiong, L. X.; Song, H. B.; Wang, Q. M. J. Agric. Food Chem. 2011, 59, 12543.

  7. [7]

     (a) Tang, B.; Guan, A. Y.; Zhao, Y.; Jiang, J. Z.; Wang, M. A.; Zhou, L. G. Chin. J. Chem. 2017, 35, 1133.
     (b) Zhao, Y.; Tang, B.; Guan, A. Y.; Wang, W. W.; Zhang, Z. H.; Wang, M. A. Synthesis 2017, 49, 4663.
     (c) Tang, B.; Yang, M. Y.; Zhao, Y.; Kong, L. Q.; Wang, W. W.; Wang, M. A. Molecules 2015, 20, 13740.

  8. [8]

     Zhao, Y.; Liu, X. L.; Wang, W. W.; Geng, R.; Wang, M. A. Synthesis 2018, 50, 4055. doi: 10.1055/s-0037-1609548

  9. [9]

     (a) Arkadi, A.; Bernocchi, E.; Burini, A.; Cacchi, S.; Marinelli, F.; Pietroni, B. Tetrahedron 1988, 44, 481.
     (b) Trost, B. M.; Muller, T. J. J.; Martinez, J. J. Am. Chem. Soc. 1995, 117, 1888.
     (c) Oh, C. H.; Park, S. J.; Ryu, J. H.; Gupta, A. K. Tetrahedron Lett. 2004, 45, 7039.
     (d) Alfonsi, M.; Arkadi, A.; Chiarini, M.; Marinelli, F. J. Org. Chem. 2007, 72, 9510.
     (e) Zhou, L.-H.; Yu, X.-Q.; Pu, L. J. Org. Chem. 2009, 74, 2103.
     (f) Ramon, R. S.; Pottier, C.; Gomez-Suarez, A.; Nolan, S. P. Adv. Synth. Catal. 2011, 353, 1575.
     (g) Yamamoto, Y.; Shibano, S.; Kurohara, T.; Shibuya, M. J. Org. Chem. 2014, 79, 4503.

  10. [10]

      (a) Peter, J.; Robert, V.; Thomas, S.; Otto, S.; Michael, B. DE 102006015467, 2007.
      (b) Lui, N.; Heinrich, J.-D. US 20110152534, 2011.
      (c) Zhao, Y.; Tang, B.; Liu, X. L.; Li, W. Z.; Huang, M. Y.; Wang, M. A. Chin. J. Org. Chem. 2017, 37, 957(in Chinese).
      (赵宇, 汤博, 刘鑫磊, 李婉祯, 黄铭一, 王明安, 有机化学, 2017, 37, 957.)
      (d) Zhao, Y.; Guan, A. Y.; Li, W. Z.; Wang, W. W.; Liu, X. L.; Wang, M. A. Chin. J. Org. Chem. 2019, 39, 1344(in Chinese).
      (赵宇, 关爱莹, 李婉祯, 王卫伟, 刘鑫磊, 王明安, 有机化学, 2019, 39, 1344.)

  11. [11]

      (a) Ogawa, A. K.; Willoughby, C. A.; Bergeron, R.; Ellsworth, K. P.; Geissler, W. M.; Myers, R. W.; Yao, J.; Harries, G.; Chapman, K. T. Bioorg. Med. Chem. Lett. 2003, 13, 3405.
      (b) Chouldhary, G.; Peddinti, R. K. Green Chem. 2011, 13, 3290.
      (c) Wang, Z.; Wang, M.; Yao, X.; Li, Y.; Tan, J.; Wang, L.; Qiao, W.; Geng, Y.; Liu, Y.; Wang, Q. Eur. J. Med. Chem. 2012, 54, 33.

  12. [12]

      Arcadi, A.; Alfonsi, M.; Marinelli, F. Tetrahedron Lett. 2009, 50, 2060. doi: 10.1016/j.tetlet.2009.02.106

• 

  Figure 1  Structures of typical 5, 5-spirocyclicfuran-2(5H)-one natural products and insecticides

  下载: 全尺寸图片 幻灯片
  

  Scheme 1  Synthetic routes of 4-allyl, or 4-aminofuran-2(5H)- ones and Michael-addition of 4-alkyl-2-ynoate with amines

  下载: 全尺寸图片 幻灯片
  

  Scheme 2  Domino reaction of N-2, 2-difluoroethyl-N-hetero- arylmethylamines with 4-hydroxyalkyl-2-ynoates

  下载: 全尺寸图片 幻灯片
  

  Scheme 3  Proposed mechanism for the catalyst-free 4-aminofuran-2(5H)-one formation

  下载: 全尺寸图片 幻灯片
  

  Figure 2  Preparation and its crystal structure of compound 8

  下载: 全尺寸图片 幻灯片

  Table 1.  Synthetic condition optimization of 3a

  Entry	Solvent	n(2a):n(1a)	Additive	T/℃	t/h	Yielda/%
  1	H2O	1:1	—	25	96	23
  2	H2O	1:1	—	25	96	42b
  3	Et2O	1:1	—	30	96	6
  4	THF	1:1	—	66	96	27
  5	DCM	1:1	—	25	96	0
  6	MeCN	1:1	—	82	96	10
  7	H2O	1:1	—	100	96	60
  8	MeOH	1:1	—	65	48	78
  9	EtOH	1:1	—	78	48	50
  10	i-PrOH	1:1	—	97	48	54
  11	n-BuOH	1:1	—	117	48	63
  12	EtOH	1:1	—	65	48	44
  13	i-PrOH	1:1	—	65	48	45
  14	n-BuOH	1:1	—	65	48	51
  15	H2O	1:1	—	65	48	73
  16	MeOH	1:1.5	—	65	48	72
  17	MeOH	1:2	—	65	48	75
  18	MeOH	1:1	Na2CO3 (1 equiv.)	65	48	41
  19	MeOH	1:1	Na2CO3 (1 equiv.)	65	48	12
  20	MeOH	1:1	Na2CO3 (1 equiv.)	65	48	46
  a Reaction conditions: 1a (0.5 mmol), 2a (0.5 mmol) in 0.5 mL of solvents. b With ultrasound irradiation.

  下载: 导出CSV

  Table 2.  Domino reaction of N-heteroarylmethyl-2, 2-difluoroethan-1-amines and 4-hydroxyalkyl-2-ynoates

  下载: 导出CSV

  Table 3.  Domino reaction of N-alkylarylmethylamine 1g~1i and 4-hydroxy-4-methyl-2-pentynoate (2a)

  下载: 导出CSV

  Table 4.  Insecticidal activities (mortality/%) of compounds 3a~3x against several insects at 600 µg•mL^－1

  Compd.	P. xylo-stella	M. sepa-rata	M. per-sicae	T. cinna-barinus
  3a	0	85	100	0
  3b	0	70	90	0
  3c	0	80	100	0
  3d	0	50	60	0
  3e	0	50	60	0
  3f	0	70	80	0
  3g	0	0	0	0
  3h	0	0	0	0
  3i	0	0	0	0
  3j	0	0	0	0
  3k	0	0	0	0
  3l	0	0	0	0
  3m	0	0	0	0
  3n	0	0	0	0
  3o	0	0	0	0
  3p	0	0	0	0
  3q	0	0	0	0
  3r	0	50	0	0
  3s	0	0	0	0
  3t	0	0	0	0
  3u	0	0	0	0
  3v	0	0	0	0
  3w	0	0	0	0
  3x	0	0	0	0
  8	0	0	0	0
  FPF	0	0	100	0

  下载: 导出CSV
•