English

• 1.   Introduction

  Pyrazolidine and pyrazoline compounds are highly valuable hereocycles existing in many natural products and bioactive compounds.^[1] Many their derivatives exhibit remarkable biological and pharmacological activities such as antitumor, ^[2] antidepressant, ^[3] anticonvulsant, ^[4] antimicrobial, ^[5] analgesic^[6] and anesthetic^[7] activities as well as acyltransferase inhibitors.^[8] Some of them have also shown potential application in material science due to their attractive photophysical properties.^[9]

  In addition, the incorporation of trifluoromethyl groups into organic molecules can lead to great changes in their physicochemical and biological propeties, such as enhanced binding affinity, lipophilicity, metabolic stability, bioavailability and so on.^[10] Thus, trifluoromethylated heterocycles have been widely applied in pharmaceutical chemistry, agrochemistry, and materials science.^[11] Among them, CF₃-substituted pyrazolines have already been proven to be highly bioactive (Figure 1).^[12] However, there have been no reports on the bioactivity investigation of CF₃-substituted pyrazolidines till now, and the synthetic methods for CF₃-substituted pyrazolidines are formidable scarce in literature.^[13] In our research works on fluorine chemistry, ^[14] we found that trifluoromethylated N-acyl- hydrazones are very stable towards air, heat and moisture, and could be easily prepared from commercially available aqueous trifluoroacetaldehyde methyl hemiacetal and N-acylhydrazons. Hence, we tried to develop them into useful trifluoromethyl building blocks for the synthesis of CF₃-substituted heterocyles. In our previous works, we found that trifluoromethylated N-acylhydrazones could act as 1, 3-dipolars to conduct [3+2] cycloaddition reactions with electron-deficient nitrolefins under basic conditions to produce trifluoromethylated pyrazolidines in good yields.^[13a] To further extend their application, we found that the trifluoromethylated N-acylhydrazones could also react with electron-rich olefins catalyzed by Lewis acid to give CF₃-substituted pyrazolidines in high yields. The pyrazolidines obtained can be further transformed into tri- fluoromethylated pyrazolines. This method is complementary to our previous basic one.

  Figure 1

  

  Figure 1.  Bioactive trifluoromethylated pyrazolines

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  2.   Results and discussion

  We examined the reaction of N'-(2, 2, 2-trifluoroethylene)- benzohydrazide (1a) and cyclopentadiene (2) catalyzed by BF₃·OEt₂ in CH₂Cl₂ at room temperature. To our delight, the [3+2] cycloaddition of 1a and 2 really occurred and the products syn-3a and anti-3a were obtained in total yield of 90% albeit with only 63:37 diastereomer ratio (Table 1, Entry 1). The relative configuration of 3a was determined by single-crystal X-ray analysis. Encouraged by this result, different solvents such as dichloroethane (DCE), tetrahydrofuran (THF), 1, 4-dioxane and toluene were screened, and it was found that DCE and CH₂Cl₂ were beneficial to the reaction (Table 1, Entries 2~5). Next, the effect of temperature on the reaction was examined in CH₂Cl₂. The yield of the product 3a was reduced greatly whether increasing the temperature or reducing the temperature, and the stereoselectivity of the reaction was neither improved (Table 1, Entries 6~8). Moreover, screening of various Lewis acids, such as Ni(ClO₄)₂·6H₂O, AlCl₃, Sc(OTf)₃, Fe(OTf)₂, Cu(OTf)₂, AgOTf, and protonic acid TfOH, indicated that Cu(OTf)₂ was the suitable one, which improved the diastereoselectivity of the product to 72:28 and the total yield is up to 91% (Table 1, Entries 9~15). Finally, effect of catalyst loading on the reaction was examined. When 20 mol% catalyst was used, the yield and diastereoselectivity of 3a were not improved, but the yield of the product 3a sharply decreased to 20% when the amount of the catalyst decreased to 5 mol% (Table 1, Entries 16 and 17). Thus, 10 mol% Cu(OTf)₂ was determined to be the suitable choice.

  Table 1

  

  Table 1.  Optimization of reaction conditions^a

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  Entry	Mole ratio of 1a:2:Lewis acid	Lewis acid	Solvent	Temp./℃	Total yieldb/%	dr (syn/anti)c
  1	1:2:0.1	BF3·OEt2	CH2Cl2	r.t.	90	62/38
  2	1:2:0.1	BF3·OEt2	(CH2Cl)2	r.t.	90	61/39
  3	1:2:0.1	BF3·OEt2	THF	r.t.	62	55/45
  4	1:2:0.1	BF3·OEt2	1, 4-Dioxane	r.t.	42	59/41
  5	1:2:0.1	BF3·OEt2	Toluene	r.t.	44	69/31
  6	1:2:0.1	BF3·OEt2	CH2Cl2	Reflux	65	65/35
  7	1:2:0.1	BF3·OEt2	CH2Cl2	0	37	58/42
  8d	1:2:0.1	BF3·OEt2	CH2Cl2	-10	17	68/32
  9	1:2:0.1	Ni(ClO4)2·6H2O	CH2Cl2	r.t.	n.r.e	—
  10	1:2:0.1	AlCl3	CH2Cl2	r.t.	n.r.e	—
  11	1:2:0.1	Sc(OTf)3	CH2Cl2	r.t.	47	71/29
  12	1:2:0.1	Cu(OTf)2	CH2Cl2	r.t.	91	72/28
  13	1:2:0.1	Fe(OTf)2	CH2Cl2	r.t.	28	46/54
  14	1:2:0.1	AgOTf	CH2Cl2	r.t.	84	60/40
  15	1:2:0.1	TfOH	CH2Cl2	r.t.	85	58/42
  16	1:2:0.2	Cu(OTf)2	CH2Cl2	r.t.	81	71/29
  17	1:2:0.05	Cu(OTf)2	CH2Cl2	r.t.	20	70/30
  a Reaction conditions: 1a (0.4 mmol), 2 (0.8 mmol), Lewis acid (10 mol%, 0.04 mmol), solvent (5 mL). b Isolated yield. c Diastereomer ratio was determined by 1H NMR spectroscopic analysis of the crude reaction mixture. d 72 h. e n.r.＝no reaction, 1a was recovered.

  With the optimized reaction conditions in hand, the substrate scope was then investigated. Firstly, various trifluoromethylated N-acylhydrazones were examined. As shown in Table 2, most of the aromatic trifluoromethylated N-acylhydrazones with either electron-withdrawing or electron-donating groups on the phenyl ring could react with cyclopentadiene to give the corresponding pyrazolidine products 3c~3j in good yields (Table 2, Entries 3~10). However, the positions of the substituents on phenyl ring had an obvious effect on the reaction. In general, when the substituents were at para- or meta-position, the reaction proceeded smoothly, and the para-substituted aromatic N-acylhydrazones gave the products in higher yields than the meta-substituted ones (Table 2, Entries 3 and 4, 6 and 7). However, when the substituents were at ortho-position, no reactions occurred (Table 2, Entries 2 and 5). In addition, trifluoromethylated N-acylhydra- zones derived from 2-naphthohydrazide and furan-2-car- bohydrazide could also be applied in the reaction to afford the corresponding products 3k and 3l in 73% and 75% yields, respectively (Table 2, Entries 11 and 12). In addition, changing aromatic N-acylhydrazones to aliphatic N-acylhydrazones provided the corresponding products 3m and 3n in good yields (Table 2, Entries 13 and 14). However, the ketone-derived N-acylhydrazones such as 2, 2, 2- trifluoroacetophenone-derived N-acylhydrazone could not afford the corresponding product, and only substrates were recovered (Table 2, Entry 15).

  Table 2

  

  Table 2.  Substrate scope of trifluoromethylated acylhydrazones^a

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  Entry	R1	R2	Product	Total yieldb/%	dr (syn/anti)c
  1	H	Ph (1a)	3a	91	72/28d
  2	H	2-CH3C6H4 (1b)	3b	n.r.e	—
  3	H	3-CH3C6H4 (1c)	3c	55	66/34d
  4	H	4-CH3C6H4 (1d)	3d	87	69/31d
  5	H	2-ClC6H4 (1e)	3e	n.r.e	—
  6	H	3-ClC6H4 (1f)	3f	62	79/21
  7	H	4-ClC6H4 (1g)	3g	97	91/9
  8	H	4-FC6H4 (1h)	3h	97	91/9
  9	H	4–O2NC6H4 (1i)	3i	77	85/15
  10	H	4-CH3OC6H4 (1j)	3j	92	84/16
  11	H	2-Naphthyl (1k)	3k	73	87/13
  12	H	2-Furyl (1l)	3l	75	85/15
  13	H	Benzyl (1m)	3m	87	76/24
  14	H	c-Hexyl (1n)	3n	89	87/13
  15	Ph	Ph (1o)	3o	n.r.e	—
  a Reaction conditions: 1 (0.4 mmol), 2 (0.8 mmol), Cu(OTf)2 (10 mol%, 0.04 mmol), CH2Cl2 (5 mL). b Isolated yields. c Determined by 1H NMR spectroscopic analysis of the crude reaction mixture. d Both isomers were isolated. e n.r.＝no reaction, 1a was recovered.

  Other alkenes such as styrene, p-methylstyrene, p-me- thoxystyrene, p-chlorostyrene, o-chlorostyrene, m-chloro- styrene and α-methylstyrene were then tested, but only styrene 4 was suitable for the [3+2] cycloaddition to give the product 5 in 71% yield with 94/6 d.r. value (Eq. 1). The structure of 5 was determined by NOESY data of 5 (see Supporting Information).

  (1)

  In order to further demonstrate the synthetic utility of the cycloaddition process, scale-up experiment and elaboration of CF₃-substituted pryazolidine 3a were conducted.We found that when the molar ratio of trifluoromethyl acyl hydrazone to cyclopentadiene was 1:5, the cycloaddition can be readily scaled up on a gram scale with maintained efficiency (Eq. 2).

  (2)

  The trifluoromethyl pyrazolidines obtained in the above [3+2] cycloaddition could be further transformed into trifluoromethylated pyrazoline derivatives 6 by oxidation reaction of C—N bond. As summarized in Table 3, trifluoromethylated pyrazolines were produced in excellent yields when pyrazolidines 3 or 5 were refluxed in ethanol in the presence of copper chloride.

  Table 3

  

  Table 3.  Transformation of the [3+2] cycloaddition products^a

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  a Reaction conditions: 3 (0.1 mmol), CuCl2 (0.1 mmol), reflux in EtOH (5 mL) for 20 min. Isolated yield.

  Finally, the mechanism is proposed in Scheme 2 based on our experiments and literature.^[15] Isomerization of trifluoromethylated N-acylhydrazones 1 gave two isomers A and B. The isomer B combined Cu(OTf)₂ to form an intermediate 7, which reacted with 1, 3-cyclopentadiene to afford a plausible transition state structure 8. The transition state 8 generated the intermediate 9. Decomposition of intermediate 8 produced final product syn-3 and the catalyst Cu(OTf)₂ (Scheme 2).

  Scheme 2

  

  Scheme 2.  Proposed mechanism for the [3+2] cycloaddition reaction

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  3.   Conclusions

  In summary, we have developed a Cu(OTf)₂-catalyzed [3+2] cycloaddition of trifluoromethylated N-acylhydra- zones and alkenes under mild conditions. In this process, stable and easily available trifluoromethylated N-acylhy- drazones were chosen as building blocks for the construction of CF₃-substituted pryazolidine and pyrazoline derivatives, which provides a facile method to incoporate the CF₃ group into heterocycles. Further studies on the use of trifluoromethylated N-acylhydrazones as trifluoromethyl building blocks for the syntesis of CF₃-substituted heterocycles are currently underway in our laboratory.

  4.   Experimental section

  4.1   Materials and methods

  The solvents were distilled by standard methods. Reagents were obtained from commercial suppliers and used without further purification unless otherwise noted. Flash column chromatography was carried out using Qingdao silica Gel (230~400 mesh). Analytical thin layer chromatography (TLC) was done using Qingdao silica gel (silica gel GF254). TLC plates were analyzed by ultraviolet (UV) light. ¹H NMR, ¹³C NMR spectra were recorded at 400 MHz or 600 MHz and 100 MHz or 150 MHz spectrome ters, respectively. ¹⁹F NMR spectra were recorded at 376 MHz spectrometers. Chemical shifts are reported as δ values relative to internal TMS (δ 0.00 for ¹H NMR), chloroform (δ 7.26 for ¹H NMR and 77.00 for ¹³C NMR). Melting points were uncorrected. The HRMS data were measured on a MALDI-TOF type of instrument for the high resolution mass spectra. Diastereomeric excesses of products were determined by ¹H NMR spectroscopic analysis of the crude reaction mixture. The substrates 1a~1p were prepared according to literature procedures.^[13]

  4.2   General procedure for the synthesis of 3 and 5

  The catalyst Cu(OTf)₂ (0.1 equiv, 0.04 mmol) was added to the solution of trifluoromethyl acylhydrazone (1.0 equiv., 0.40 mmol) in dry CH₂Cl₂ (5.0 mL), and then freshly cracked cyclopentadiene or styrene (2.0 equiv., 0.80 mmol) was added to the mixture at room temperature and stirring was continued at the same temperature for 54 h. The saturated sodium bicarbonate solution (10 mL) was poured into the mixture and stirred for 10 min, and the mixture was extracted with CH₂Cl₂ (10 mL×3). The combined organic extracts were dried (MgSO₄) and concentrated. CH₂Cl₂ was then removed under vacuum and the crude reaction mixture was directly loaded on a silica column. The column was eluted by using ether/acetone mixture to obtain pure racemic [3+2] cycloaddition products 3 and 5.

  ((3R, 3aS, 6aS)-3-Trifluoromethyl-2, 3, 3a, 4-tetrahydrocyc-lopenta[c]pyrazol-1(6aH)-yl)(phenyl)methanone (3a): White solid, 70.6 mg, total yield 91%, dr 72:28. m.p. 129~131 ℃; ¹H NMR (600 MHz, CDCl₃) δ: 7.73 (d, J＝6.0 Hz, 2H), 7.45~7.44 (m, 1H), 7.40~7.38 (m, 2H), 6.01 (s, 1H), 5.83 (s, 1H), 5.65 (br, 1H), 4.48 (br, 1H), 3.72 (s, 1H), 3.34 (s, 1H), 2.69 (d, J＝18.0 Hz, 1H), 2.57~2.53 (m, 1H); ¹³C NMR (150 MHz, CDCl₃) δ: 168.6, 135.2, 134.2, 130.7, 128.9, 127.7, 127.6, 123.8 (q, J_C—F＝279.0 Hz), 69.5, 64.1 (br), 42.1, 32.2; ¹⁹F NMR (376 MHz, CDCl₃) δ: -72.68 (s); HRMS (ESI) calcd for C₁₄H₁₃- F₃N₂NaO [M+Na]⁺ 305.0872, found 305.0876.

  ((3R, 3aS, 6aS)-3-Trifluoromethyl-2, 3, 3a, 4-tetrahydrocyc-lopenta[c]pyrazol-1(6aH)-yl)(3-methylphenyl)methanone (syn-3c): White solid, 43.0 mg, total yield 55%, dr 66:34. m.p. 89~91 ℃; ¹H NMR (600 MHz, CDCl₃) δ: 7.51~7.49 (m, 2H), 7.29~7.25 (m, 2H), 6.00 (s, 1H), 5.82 (s, 1H), 5.63 (br, 1H), 4.47 (br, 1H), 3.74~3.70 (m, 1H), 3.36~3.31 (m, 1H), 2.70 (d, J＝18.0 Hz, 1H), 2.55 (dd, J＝18.6 Hz, 9.6 Hz, 1H), 2.38 (s, 3H); ¹³C NMR (150 MHz, CDCl₃) δ: 169.0, 137.6, 135.2, 134.2, 131.4, 129.4, 127.7, 127.6, 125.9, 123.9 (q, J_C—F＝277.5 Hz), 69.5, 64.1 (br), 42.2, 32.3, 21.3; ¹⁹F NMR (376 MHz, CDCl₃) δ: -67.47 (s); HRMS (ESI) calcd for C₁₅H₁₅F₃N₂NaO [M+ Na]⁺ 319.1029, found 319.1038.

  ((3R, 3aR, 6aR)-3-Trifluoromethyl-2, 3, 3a, 4-tetrahydrocyc- lopenta[c]pyrazol-1-(6aH)-yl)(3-methylphenyl)methanone (anti-3c): White solid, 5.2 mg, yield 13%. m.p. 79~81 ℃; ¹H NMR (600 MHz, CDCl₃) δ: 7.47 (s, 2H), 7.28~7.22 (m, 2H), 5.99 (m, 1H), 5.86 (s, 1H), 5.78 (s, 1H), 4.66 (s, 1H), 3.40 (s, 1H), 3.28 (t, J＝7.8 Hz 1H), 3.90~3.86 (m, 1H), 2.40 (d, J＝18.0 Hz, 1H), 2.36 (s, 3H); HRMS (ESI) calcd for C₁₅H₁₅F₃N₂NaO [M+Na]⁺ 319.1029, found 319.1024.

  ((3R, 3aS, 6aS)-3-Trifluoromethyl-2, 3, 3a, 4-tetrahydrocyc-lopenta[c]pyrazol-1(6aH)-yl)(4-methylphenyl)methanone (syn-3d): White solid, 71.1 mg, total yield 87%, dr 69:31. m.p. 139~141 ℃; ¹H NMR (600 MHz, CDCl₃) δ: 7.65 (d, J＝7.8 Hz, 2H), 7.20 (d, J＝7.8 Hz, 2H), 6.01~6.00 (m, 1H), 5.83~5.82 (q, J＝2.4 Hz, 1H), 5.65 (br, 1H), 4.55 (br, 1H), 3.74~3.61 (m, 1H), 3.35~3.30 (m, 1H), 2.68 (d, J＝18.6 Hz, 1H), 2.55 (dd, J＝18.6 Hz, 9.6 Hz, 1H), 2.38 (s, 3H); ¹³C NMR (150 MHz, CDCl₃) δ: 168.7, 141.1, 135.1, 131.2, 129.1, 128.4, 127.8, 123.5 (q, J_C—F＝279.0 Hz), 69.5, 64.5 (br), 42.1, 32.3, 21.4. ¹⁹F NMR (376 MHz, CDCl₃) δ: -67.49 (s); HRMS (ESI) calcd for C₁₅H₁₅F₃N₂NaO [M+Na]⁺ 319.1029, found 319.1020.

  ((3R, 3aR, 6aR)-3-Trifluoromethyl-2, 3, 3a, 4-tetrahydrocyc- lopenta[c]pyrazol-1-(6aH)-yl)(4-methylphenyl)methanone (anti-3d): White solid, 8.1 mg, yield 22%. m.p. 129~131 ℃; ¹H NMR (600 MHz, CDCl₃) δ: 7.61 (s, 2H), 7.18 (d, J＝7.8 Hz, 2H), 6.00 (s, 1H), 5.90 (s, 1H), 5.79 (s, 1H), 4.61 (s, 1H), 3.41 (s, 1H), 3.28 (t, J＝7.8 Hz, 1H), 2.90~2.86 (m, 1H), 2.41 (d, J＝18.0 Hz, 1H), 2.38 (s, 3H); HRMS (ESI) calcd for C₁₅H₁₅F₃N₂NaO [M+Na]⁺ 319.1029, found 319.1015.

  ((3R, 3aS, 6aS)-3-Trifluoromethyl-2, 3, 3a, 4-tetrahydrocyc-lopenta[c]pyrazol-1(6aH)-yl)(3-chlorophenyl)methanone (3f): White solid, 62.0 mg, total yield 62%, dr 79:21. m.p. 77~79 ℃; ¹H NMR (600 MHz, CDCl₃) δ: 7.72 (s, 1H), 7.61 (d, J＝7.8 Hz, 1H), 7.42 (d, J＝7.8 Hz, 1H), 7.32 (t, J＝7.8 Hz, 1H), 6.02~6.01 (m, 1H), 5.81~5.80 (m, 1H), 5.67 (br, 1H), 4.41 (br, 1H), 3.74~3.67 (m, 1H), 3.38~3.33 (m, 1H), 2.68 (d, J＝18.6 Hz, 1H), 2.57 (dd, J＝18.6 Hz, 9.6 Hz, 1H); ¹³C NMR (150 MHz, CDCl₃) δ: 167.2, 135.9, 135.4, 133.7, 130.7, 129.1, 129.0, 127.4, 127.1, 123.7 (q, J_C—F＝277.5 Hz), 69.5, 64.5 (br), 42.1, 32.2; ¹⁹F NMR (376 MHz, CDCl₃) δ: -67.42 (s); HRMS (ESI) calcd for C₁₄H₁₂ClF₃N₂NaO [M+Na]⁺ 339.0482, found 339.0488.

  ((3R, 3aS, 6aS)-3-Trifluoromethyl-2, 3, 3a, 4-tetrahydrocyc-lopenta[c]pyrazol-1(6aH)-yl)(4-chlorophenyl)methanone (3g): White solid, 111.8 mg, total yield 97%, dr 91:9. m.p. 134~136 ℃; ¹H NMR (600 MHz, CDCl₃) δ: 7.71 (d, J＝7.8 Hz, 2H), 7.36 (d, J＝8.4 Hz, 2H), 6.02~6.01 (m, 1H), 5.82~5.81 (m, 1H), 5.68 (br, 1H), 4.46 (br, 1H), 3.72~3.67 (m, 1H), 3.37~3.33 (m, 1H), 2.67 (d, J＝18.6 Hz, 1H), 2.59~2.54 (m, 1H); ¹³C NMR (150 MHz, CDCl₃) δ: 167.6, 136.9, 135.4, 132.4, 130.6, 128.0, 127.5, 123.7 (q, J_C—F＝277.5 Hz), 69.5, 64.6 (br), 42.0, 32.2; ¹⁹F NMR (376 MHz, CDCl₃) δ: -68.25 (s); HRMS (ESI) calcd for C₁₄H₁₂ClF₃N₂NaO [M+Na]⁺ 339.0482, found 339.0484.

  ((3R, 3aS, 6aS)-3-Trifluoromethyl-2, 3, 3a, 4-tetrahydrocyc-lopenta[c]pyrazol-1(6aH)-yl)(4-fluorophenyl)methanone (3h): White solid, 106.0 mg, total yield 97%, dr 91:9. m.p. 141~143 ℃; ¹H NMR (600 MHz, CDCl₃) δ: 7.69~7.62 (m, 2H), 7.36~7.30 (m, 4H), 6.85 (s, 1H), 6.66 (d, J＝14.4 Hz, 1H), 6.34 (s, 1H), 4.95 (s, 1H), 3.85~3.81 (m, 1H), 3.35~3.33 (m, 1H); ¹³C NMR (150 MHz, CDCl₃) δ: 167.5, 164.1 (d, J＝250.5 Hz), 135.3, 131.6 (d, J＝4.5 Hz), 130.1, 127.6, 123.8 (q, J_C—F＝279.0 Hz), 114.7 (d, J＝22.5 Hz), 69.6, 64.5 (br), 42.0, 32.2; ¹⁹F NMR (376 MHz, CDCl₃) δ: -70.03 (s), -111.82 (s); HRMS (ESI) calcd for C₁₄H₁₂F₄N₂NaO [M+Na]⁺ 323.0778, found 323.0774.

  ((3R, 3aS, 6aS)-3-Trifluoromethyl-2, 3, 3a, 4-tetrahydrocyc-lopenta[c]pyrazol-1(6aH)-yl)(4-nitrophenyl)methanone (3i): White solid. 85.7 mg, total yield 77%, dr 85:15. m.p. 126~128 ℃; ¹H NMR (600 MHz, CDCl₃) δ: 8.24 (d, J＝8.4 Hz, 2H), 7.87 (d, J＝8.4 Hz, 2H), 6.05~6.04 (m, 1H), 5.84 (s, 1H), 5.73 (br, 1H), 4.38 (br, 1H), 3.73~3.69 (m, 1H), 3.43~3.38 (m, 1H), 2.69 (d, J＝18.6 Hz, 1H), 2.60 (dd, J＝18.0 Hz, 9.0 Hz, 1H); ¹³C NMR (150 MHz, CDCl₃) δ: 167.2, 148.8, 140.2, 135.8, 129.9, 127.2, 123.6 (q, J_C—F＝274.5 Hz), 122.9, 69.6, 64.8 (br), 42.2, 32.1; ¹⁹F NMR (376 MHz, CDCl₃) δ: -67.37 (s); HRMS (ESI) calcd for C₁₄H₁₂F₃N₃NaO₃ [M+Na]⁺ 350.0723, found 350.0722.

  ((3R, 3aS, 6aS)-3-Trifluoromethyl-2, 3, 3a, 4-tetrahydrocyc-lopenta[c]pyrazol-1(6aH)-yl)(4-methoxyphenyl)methanone (3j): White solid, 96.5 mg, total yield 92%, dr 84:16. m.p. 118~120 ℃; ¹H NMR (600 MHz, CDCl₃) δ: 7.81 (d, J＝8.4 Hz, 2H), 6.89 (d, J＝9.0 Hz, 2H), 6.00~5.99 (m, 1H), 5.83~5.81 (m, 1H), 5.67 (br, 1H), 4.62 (br, 1H), 3.84 (s, 3H), 3.74~3.67 (m, 1H), 3.35~3.30 (m, 1H), 2.68 (d, J＝18.0 Hz, 1H), 2.55 (dd, J＝18.0 Hz, 9.0 Hz, 1H). ¹³C NMR (150 MHz, CDCl₃) δ: 168.1, 161.6, 135.0, 131.3, 127.8, 126.1, 123.8 (q, J_C—F＝277.5 Hz), 112.9, 69.6, 64.4 (br), 55.2, 41.9, 32.2. ¹⁹F NMR (376 MHz, CDCl₃) δ: -7.46 (s); HRMS (ESI) calcd for C₁₄H₁₅F₃N₂NaO [M+ Na]⁺ 335.0978, found 335.0975.

  ((3R, 3aS, 6aS)-3-Trifluoromethyl-2, 3, 3a, 4-tetrahydrocyc-lopenta[c]pyrazol-1(6aH)-yl)(2-naphthyl)methanoe (3k): White solid, 84.4 mg, total yield 73%, dr 87:13. m.p. 171~173 ℃; ¹H NMR (600 MHz, CDCl₃) δ: 8.27 (s, 1H), 7.89 (d, J＝7.8 Hz, 1H), 7.84 (t, J＝7.2 Hz, 2H), 7.79 (d, J＝8.4 Hz, 1H), 7.56~7.50 (m, 2H), 6.02 (s, 1H), 5.88~5.87 (m, 1H), 5.72 (br, 1H), 4.62 (br, 1H), 3.78~3.71 (m, 1H), 3.38~3.34 (m, 1H), 2.70 (d, J＝18.6 Hz, 1H), 2.56 (dd, J＝18.6 Hz, 9.6 Hz, 1H); ¹³C NMR (150 MHz, CDCl₃) δ: 168.8, 135.3, 134.3, 132.3, 131.5, 129.6, 128.9, 127.7, 127.6, 127.4, 127.3, 126.4, 125.7, 123.9 (q, J_C—F＝279.0Hz), 69.6, 64.5 (br), 41.2, 32.3; ¹⁹F NMR (376 MHz, CDCl₃) δ: -67.44 (s); HRMS (ESI) calcd for C₁₈H₁₅- F₃N₂NaO [M+Na]⁺ 355.1029, found 355.1041.

  ((3R, 3aS, 6aS)-3-Trifluoromethyl-2, 3, 3a, 4-tetrahydrocyc-lopenta[c]pyrazol-1(6aH)-yl)(2-furyl)methanone (3l): White solid, 69.4 mg, total yield 75%, dr 85:15. m.p. 123~125 ℃; ¹H NMR (600 MHz, CDCl₃) δ: 8.09 (s, 1H), 7.60 (s, 1H), 7.11 (t, J＝3.6 Hz, 1H), 6.80 (t, J＝3.6 Hz, 2H), 6.42 (d, J＝5.4 Hz, 1H), 4.22 (s, 1H), 3.20 (s, 1H), 2.49 (q, J＝7.8 Hz, 1H), 2.19 (d, J＝9.0 Hz, 1H), 1.61 (d, J＝9.0 Hz, 1H); ¹³C NMR (150 MHz, CDCl₃) δ: 164.2, 140.4, 135.0, 133.7, 133.1, 132.4, 126.2, 125.2 (q, J_C—F＝279.0 Hz), 68.3, 67.3 (q, J_C—F＝30.0 Hz), 45.4, 44.2; ¹⁹F NMR (376 MHz, CDCl₃) δ: -78.19 (s); HRMS (ESI) calcd for C₁₂H₁₁F₃N₂NaO₂ [M+Na]⁺ 295.0665, found 295.0666.

  ((3R, 3aS, 6aS)-3-Trifluoromethyl-2, 3, 3a, 4-tetrahydrocyc-lopenta[c]pyrazol-1(6aH)-yl)(benzyl)methanone (3m): Colorless liquid, 78.4 mg, total yield 87%, dr 76:24; ¹H NMR (600 MHz, CDCl₃) δ: 7.33 (d, J＝7.8 Hz, 2H), 7.30 (t, J＝7.2 Hz, 2H), 7.23 (t, J＝7.2 Hz, 1H), 5.91 (s, 1H), 5.69 (s, 1H), 5.68 (d, J＝3.0 Hz, 1H), 4.20 (d, J＝13.2 Hz, 1H), 3.91 (d, J＝13.8 Hz, 1H), 3.76 (d, J＝13.8 Hz, 1H), 3.39~3.34 (m, 1H), 3.24~3.20 (m, 1H), 2.57 (d, J＝18.6 Hz, 1H), 2.49 (dd, J＝18.0, 9.0 Hz, 1H); ¹³C NMR (150 MHz, CDCl₃) δ: 171.4, 135.1, 134.8, 129.3, 128.5, 127.7, 126.9, 123.8 (q, J_C—F＝277.5 Hz), 68.7, 64.4 (q, J＝28.7 Hz), 42.6, 41.0, 32.0. ¹⁹F NMR (376 MHz, CDCl₃) δ: -67.28 (s); HRMS (ESI) calcd for C₁₅H₁₅F₃N₂NaO [M+ Na]⁺ 319.1029, found 319.1026.

  ((3R, 3aS, 6aS)-3-Trifluoromethyl-2, 3, 3a, 4-tetrahydrocyc-lopenta[c]pyrazol-1(6aH)-yl)(c-hexyl)methanone (3n): White solid, 89.3 mg, total yield 89%, dr 87:13. m.p. 64~66 ℃; ¹H NMR (600 MHz, CDCl₃) δ: 5.93 (s, 1H), 5.71~5.69 (m, 1H), 5.51 (d, J＝6.6 Hz, 1H), 3.63~3.56 (m, 1H), 3.31~3.26 (m, 1H), 2.90 (t, J＝12.0 Hz, 1H), 2.61 (d, J＝18.0 Hz, 1H), 2.54~2.49 (m, 1H), 1.78~1.66 (m, 6H), 1.47~1.42 (m, 2H), 1.31 (t, J＝3.0 Hz, 1H), 1.29 (t, J＝3.6 Hz, 1H), 1.27~1.25 (m, 1H); ¹³C NMR (150 MHz, CDCl₃) δ: 176.4, 134.5, 128.0, 123.9 (q, J_C—F＝279.0 Hz), 68.2, 64.9 (q, J＝28.5 Hz), 42.4, 41.1, 32.0, 29.5, 28.4, 25.8, 25.7, 25.6; ¹⁹F NMR (376 MHz, CDCl₃) δ: -67.36 (s); HRMS (ESI) calcd for C₁₄H₁₉F₃N₂NaO [M+Na]⁺ 311.1342, found 311.1345.

  ((3R, 5R)-5-Phenyl-3-(trifluoromethyl)pyrazolidin-1-yl)-(4-chlorophenyl)methanone (5): Colorless liquid, 94.5 mg, total yield 71%, dr 94:6; ¹H NMR (400 MHz, CDCl₃) δ: 7.54 (s, 2H), 7.40~7.26 (m, 8H), 5.39 (br, 1H), 3.91~3.84 (m, 1H), 2.97~2.90 (m, 1H), 2.36~2.29 (m, 1H); ¹³C NMR (150 MHz, CDCl₃) δ: 168.4, 140.9, 137.3, 132.0, 130.1, 129.0, 128.3, 127.8, 125.7, 124.1 (q, J_C—F＝274.5 Hz), 60.8, 59.7 (br), 36.8; ¹⁹F NMR (376 MHz, CDCl₃) δ: -74.29 (s); HRMS (ESI) calcd for C₁₇H₁₄ClF₃N₂NaO [M+Na]⁺ 377.0635, found 377.0639.

  4.3   General procedure for the synthesis of 6

  A solution of trifluoromethylated pyrazolidines 3 (0.10 mmol) and CuCl₂ (0.10 mmol) in EtOH (5 mL) was stirred at reflux for 20 min. The reaction mixture was cooled to room temperature. The solid was filtered from the reaction mixture. The filtrate was concentrated under vacuum. Purification of the residue by silica gel column chromatography using petroleum ether:acetone (V:V＝4:1) as the eluent furnished the products 6.

  ((3a, 6aS)-3-Trifluoromethyl-3a, 4-dihydrocyclopenta[c]-pyrazol-1(6aH)-yl)(phenyl)methanone (6a): Colorless liquid, 26.8 mg, yield 96%. ¹H NMR (600 MHz, CDCl₃) δ: 7.87 (d, J＝7.2 Hz, 2H), 7.49 (t, J＝6.0 Hz, 1H), 7.42 (t, J＝7.8 Hz, 2H), 6.15 (s, 1H), 6.01~6.00 (m, 1H), 5.80 (d, J＝10.0 Hz, 1H), 4.03 (t, J＝10.2 Hz, 1H), 2.87 (m, J＝18.0 Hz, 9.0 Hz, 1H), 2.81 (d, J＝17.4 Hz, 1H); ¹³C NMR (150 MHz, CDCl₃) δ: 166.9, 147.7 (q, J_C—F＝36.0 Hz), 133.1, 132.9, 131.5, 129.9, 127.8, 127.7, 120.2 (q, J_C—F＝270.0 Hz), 71.3, 45.2, 36.6; ¹⁹F NMR (376 MHz, CDCl₃) δ: -65.68 (s); HRMS (ESI) calcd for C₁₄H₁₁F₃N₂NaO [M+Na]⁺ 303.0716, found 303.0722.

  ((3aR, 6aS)-3-Trifluoromethyl-3a, 4-dihydrocyclopenta[c]-pyrazol-1(6aH)-yl)(4-methyiphenyl)methanone (6b): Colorless liquid, 28.2 mg, yield 96%. ¹H NMR (400 MHz, CDCl₃) δ: 7.79 (d, J＝8.0 Hz, 2H), 7.21 (d, J＝8.0 Hz, 2H), 6.15~6.12 (m, 1H), 6.00~5.97 (m, 1H), 5.78 (d, J＝10.0 Hz, 1H), 4.03~3.98 (m, 1H), 2.89~2.76 (m, 2H), 2.39 (s, 3H); ¹³C NMR (150 MHz, CDCl₃) δ: 166.8, 147.4 (q, J_C—F＝36.0 Hz), 142.1, 133.0, 130.0, 129.9, 128.5, 127.7, 120.3 (q, J_C—F＝270.0 Hz), 71.3, 45.0, 36.6, 21.5; ¹⁹F NMR (376 MHz, CDCl₃) δ: -65.67 (s); HRMS (ESI) calcd for C₁₅H₁₃F₃N₂NaO [M+Na]⁺ 317.0872, found 317.0878.

  ((3aR, 6aS)-3-Trifluoromethyl-3a, 4-dihydrocyclopenta-[c]pyrazol-1(6aH)-yl)(3-chlorophenyl)methanone (6c): Co- lorless liquid, 28.4 mg, yield 94%. ¹H NMR (600 MHz, CDCl₃) δ: 7.86 (s, 1H), 7.75 (d, J＝7.8 Hz, 1H), 7.60 (d, J＝7.8 Hz, 1H), 7.35 (t, J＝7.8 Hz, 1H), 6.14~6.13 (m, 1H), 6.02~6.01 (m, 1H), 5.78 (d, J＝10.2 Hz, 1H), 4.04 (t, J＝12.0 Hz, 1H), 2.88 (dd, J＝18.0, 9.0 Hz, 1H), 2.81 (d, J＝18.0 Hz, 1H); ¹³C NMR (150 MHz, CDCl₃) δ: 165.4, 147.9 (q, J_C—F＝36.0 Hz), 134.6, 133.9, 133.4, 131.5, 130.0, 129.1, 128.1, 127.4, 119.8 (q, J_C—F＝270.0 Hz), 71.4, 45.2, 36.6; ¹⁹F NMR (376 MHz, CDCl₃) δ: -65.76 (s); HRMS (ESI) calcd for C₁₄H₁₀ClF₃N₂NaO [M+ Na]⁺ 337.0326, found 337.0331.

  ((3aR, 6aS)-3-Trifluoromethyl-3a, 4-dihydrocyclopenta[c]-pyrazol-1(6aH)-yl)(4-fluorophenyl)methanone (6d): Co- lorless liquid, 29.2 mg, yield 98%. ¹H NMR (600 MHz, CDCl₃) δ: 7.95~7.93 (m, 2H), 7.09 (t, J＝9.0 Hz, 2H), 6.14~6.13 (m, 1H), 6.02~6.00 (m, 1H), 5.79 (d, J＝9.6 Hz, 1H), 4.02 (t, J＝10.2 Hz, 1H), 2.88 (dd, J＝18.0, 9.0 Hz, 1H), 2.79 (d, J＝17.4 Hz, 1H); ¹³C NMR (150 MHz, CDCl₃) δ: 165.6, 164.7 (d, J＝250.5 Hz), 147.9 (q, J_C—F＝36.0 Hz), 133.3, 132.6 (d, J＝9.0 Hz), 128.9 (d, J＝3.0 Hz), 127.6, 120.2 (q, J＝270.0 Hz), 115.0 (d, J_C—F＝21.0 Hz), 71.4, 45.2, 36.6; ¹⁹F NMR (376 MHz, CDCl₃) δ: -65.74 (s), -107.91 (s); HRMS (ESI) calcd for C₁₄H₁₀- F₄N₂NaO [M+Na]⁺ 321.0621, found 321.0625.

  ((3aR, 6aS)-3-Trifluoromethyl-3a, 4-dihydrocyclopenta[c]-pyrazol-1(6aH)-yl)(4-methoxyphenyl)methanone (6e): Co- lorless liquid, 30.1 mg, yield 97%. ¹H NMR (400 MHz, CDCl₃) δ: 7.94 (d, J＝6.0 Hz, 2H), 6.91 (d, J＝5.2 Hz, 2H), 6.14~6.13 (m, 1H), 6.00~5.99 (m, 1H), 5.79 (d, J＝6.8 Hz, 1H), 4.00 (t, J＝6.8 Hz, 1H), 3.85 (s, 3H), 2.87 (dd, J＝18.0, 9.0 Hz, 1H), 2.80 (d, J＝17.4 Hz, 1H); ¹³C NMR (150 MHz, CDCl₃) δ: 166.0, 162.3, 147.2 (q, J_C—F＝36.0 Hz), 132.9, 132.2, 127.8, 124.9, 120.3 (q, J_C—F＝270.0 Hz), 113.0, 71.4, 55.3, 44.9, 36.6; ¹⁹F NMR (376 MHz, CDCl₃) δ: -65.64 (s); HRMS (ESI) calcd for C₁₅H₁₃F₃N₂NaO [M+Na]⁺ 333.0821, found 333.0815.

  ((3aR, 6aS)-3-Trifluoromethyl-3a, 4-dihydrocyclopenta[c]-pyrazol-1(6aH)-yl)(2-furyl)methanone (6f): White solid, 25.1 mg, yield 93%, m.p. 133~135 ℃; ¹H NMR (600 MHz, CDCl₃) δ: 7.64 (dd, J＝2.4, 1.2 Hz, 1H), 7.45 (dd, J＝1.2, 0.6 Hz, 1H), 6.53 (dd, J＝5.4, 2.4 Hz, 1H), 6.13~6.10 (m, 1H), 6.01~5.98 (m, 1H), 5.77 (d, J＝15.6 Hz, 1H), 4.06~4.00 (m, 1H), 2.89~2.84 (m, 1H), 2.83~2.78 (m, 1H); ¹³C NMR (150 MHz, CDCl₃) δ: 156.2, 148.0 (q, J_C—F＝36.0 Hz), 146.1, 145.1, 133.2, 127.6, 120.3 (q, J_C—F＝267.0 Hz), 119.9, 111.8, 71.2, 45.0, 36.6. ¹⁹F NMR (376 MHz, CDCl₃) δ: -65.82 (s); HRMS (ESI) calcd for C₁₂H₉F₃N₂NaO₂ [M+Na]⁺ 293.0508, found 293.0521.

  (R)-(3-Trifluoromethyl-5-phenyl-4, 5-dihydro-1H-pyrazo- l-1-yl)(4-chlorophenyl)methanone (6g): Colorless liquid, 27.8 mg, yield 93%. ¹H NMR (600 MHz, CDCl₃) δ: 7.86 (d, J＝8.4 Hz, 2H), 7.40 (d, J＝9.0 Hz, 2H), 7.37 (d, J＝7.8 Hz, 2H), 7.32 (t, J＝7.8 Hz, 1H), 7.28 (d, J＝7.2 Hz, 2H), 5.82 (dd, J＝12.0, 6.0 Hz, 1H), 3.66~3.61 (m, 1H), 3.07~3.03 (m, 1H); ¹³C NMR (150 MHz, CDCl₃) δ: 166.0, 145.1 (q, J_C—F＝37.5 Hz), 140.2, 138.1, 131.5, 131.1, 129.2, 128.4, 128.2, 125.6, 119.7 (q, J_C—F＝270.0 Hz), 62.3, 39.5; ¹⁹F NMR (376 MHz, CDCl₃) δ: -68.61 (s); HRMS (ESI) calcd for C₁₅H₁₂F₃N₂NaO [M+Na]⁺ 375.0482, found 375.0488.

  Supporting Information  Copies of ¹H NMR, ¹³C NMR, ¹⁹F NMR spectra and the HRMS data of compounds 3, 5 and 6; X-ray Structure data of syn-3a (CCDC: 1570212) and anti-3a (CCDC: 1570213). The Supporting Information is available free of charge via the Internet at http://sioc-journal.cn/.

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  Figure 1  Bioactive trifluoromethylated pyrazolines

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  Scheme 2  Proposed mechanism for the [3+2] cycloaddition reaction

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  Table 1.  Optimization of reaction conditions^a

  Entry	Mole ratio of 1a:2:Lewis acid	Lewis acid	Solvent	Temp./℃	Total yieldb/%	dr (syn/anti)c
  1	1:2:0.1	BF3·OEt2	CH2Cl2	r.t.	90	62/38
  2	1:2:0.1	BF3·OEt2	(CH2Cl)2	r.t.	90	61/39
  3	1:2:0.1	BF3·OEt2	THF	r.t.	62	55/45
  4	1:2:0.1	BF3·OEt2	1, 4-Dioxane	r.t.	42	59/41
  5	1:2:0.1	BF3·OEt2	Toluene	r.t.	44	69/31
  6	1:2:0.1	BF3·OEt2	CH2Cl2	Reflux	65	65/35
  7	1:2:0.1	BF3·OEt2	CH2Cl2	0	37	58/42
  8d	1:2:0.1	BF3·OEt2	CH2Cl2	-10	17	68/32
  9	1:2:0.1	Ni(ClO4)2·6H2O	CH2Cl2	r.t.	n.r.e	—
  10	1:2:0.1	AlCl3	CH2Cl2	r.t.	n.r.e	—
  11	1:2:0.1	Sc(OTf)3	CH2Cl2	r.t.	47	71/29
  12	1:2:0.1	Cu(OTf)2	CH2Cl2	r.t.	91	72/28
  13	1:2:0.1	Fe(OTf)2	CH2Cl2	r.t.	28	46/54
  14	1:2:0.1	AgOTf	CH2Cl2	r.t.	84	60/40
  15	1:2:0.1	TfOH	CH2Cl2	r.t.	85	58/42
  16	1:2:0.2	Cu(OTf)2	CH2Cl2	r.t.	81	71/29
  17	1:2:0.05	Cu(OTf)2	CH2Cl2	r.t.	20	70/30
  a Reaction conditions: 1a (0.4 mmol), 2 (0.8 mmol), Lewis acid (10 mol%, 0.04 mmol), solvent (5 mL). b Isolated yield. c Diastereomer ratio was determined by 1H NMR spectroscopic analysis of the crude reaction mixture. d 72 h. e n.r.＝no reaction, 1a was recovered.

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  Table 2.  Substrate scope of trifluoromethylated acylhydrazones^a

  Entry	R1	R2	Product	Total yieldb/%	dr (syn/anti)c
  1	H	Ph (1a)	3a	91	72/28d
  2	H	2-CH3C6H4 (1b)	3b	n.r.e	—
  3	H	3-CH3C6H4 (1c)	3c	55	66/34d
  4	H	4-CH3C6H4 (1d)	3d	87	69/31d
  5	H	2-ClC6H4 (1e)	3e	n.r.e	—
  6	H	3-ClC6H4 (1f)	3f	62	79/21
  7	H	4-ClC6H4 (1g)	3g	97	91/9
  8	H	4-FC6H4 (1h)	3h	97	91/9
  9	H	4–O2NC6H4 (1i)	3i	77	85/15
  10	H	4-CH3OC6H4 (1j)	3j	92	84/16
  11	H	2-Naphthyl (1k)	3k	73	87/13
  12	H	2-Furyl (1l)	3l	75	85/15
  13	H	Benzyl (1m)	3m	87	76/24
  14	H	c-Hexyl (1n)	3n	89	87/13
  15	Ph	Ph (1o)	3o	n.r.e	—
  a Reaction conditions: 1 (0.4 mmol), 2 (0.8 mmol), Cu(OTf)2 (10 mol%, 0.04 mmol), CH2Cl2 (5 mL). b Isolated yields. c Determined by 1H NMR spectroscopic analysis of the crude reaction mixture. d Both isomers were isolated. e n.r.＝no reaction, 1a was recovered.

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  Table 3.  Transformation of the [3+2] cycloaddition products^a

  a Reaction conditions: 3 (0.1 mmol), CuCl2 (0.1 mmol), reflux in EtOH (5 mL) for 20 min. Isolated yield.

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