Regioselective synthesis of fluoroalkylated [1,2,3]-triazoles by Huisgen cycloaddition

Journal of Fluorine Chemistry 125 (2004) 1415–1423

Regioselective synthesis of fluoroalkylated [1,2,3]-triazoles by Huisgen cycloaddition Yong-Ming Wu*, Juan Deng, Xiang Fang, Qing-Yun Chen* Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Rd. Shanghai 200032, China Received 22 December 2003; received in revised form 23 February 2004; accepted 24 February 2004 Available online 14 August 2004

Abstract A series of fluoroalkylated 1,4-disubstituted [1,2,3]-triazoles were synthesized by the 1,3-dipolar cycloaddition of fluoroalkylated azides with terminal alkynes in the presence of Cu(I) salt as catalyst at room temperature. All the reactions were performed in highly regioselective with 1,4-disubstituted, no 1,5-disubstituted product was formed. For aryl or alkyl-alkyne, triethylamine should be used as ligand. But for propiolic ester(amide), triethylamine couldn’t be used, otherwise no products was formed. A mechanism of Cu(I) inserting the internal alkyne was suggested. # 2004 Elsevier B.V. All rights reserved. Keywords: Fluoroalkylazide; 1,3-Dipolar cycloaddition; 1,4-Disubstituted 1,2,3-triazole; Internal alkyne; Propiolic ester(amide); Regioselective

1. Introduction [1,2,3]-Triazoles have found wide use in pharmaceuticals, agrochemicals, dyes, photographic materials and corrosion inhibition etc. [1]. For example, there are numerous examples in the literature including anti-HIV activity [2], antimicrobial activity against Gram positive bacteria [3], selective b3 adrenergic receptor agonism by means of triazole compounds [4]. Several methods have been described for the synthesis of [1,2,3]-triazoles. Among them, the most important and useful one is the cycloaddition of azide with alkyne [5]. However, this reaction usually needs elevated temperature and also forms a mixture of 1,4 and 1,5 regioisomers for unsymmetrical alkynes. Recently, studies on 1,4 versus 1,5 regioselectivity were reported. Sharpless [6] used Cu(I) salt as a catalyst to promote the reaction of azide with terminal alkynes to give in high regioselectivity 1,4-substituted products. Meldal [7] also regioselectively synthesized 1,4-substituted [1,2,3]-triazoles by 1,3-dipolar reaction of azides with polymer-supported terminal alkynes. It has been known for some time that fluorine atom can lead to unexpected results on biological activity arising due to the *

Corresponding authors. Tel.: þ86-21-64163300; fax: þ86-21-64166128. E-mail address: [email protected] (Y.-M. Wu). 0022-1139/$ – see front matter # 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.jfluchem.2004.02.016

special properties of the fluorine atom, such as the highest electonagetivety of fluorine and high carbon-fluorine bond energy [8]. However, till now only few reports recorded the synthesis of fluoroalkylated triazoles. Lermontov [9] synthesized a mixture of 1,4- and 1,5-disubstituted fluoroalkylated triazoles by the reaction between fluoroalkylazides and t erminal alkynes at elevated temperature. Zhu [10] reported a stepwise method to prepare 4-fluoacetylated 1H-1,2,3triazoles. In light of the importance of fluorinated triazoles, it is desired to develop a new and convenient method for synthesizing fluoroalkylated triazoles with high regiospecificity. Herein, we present a method for the synthesis of 1,1-dihydro-fluoroalkylazides and their regiospecific reaction with terminal alkynes in the presence of Cu(I) salt as catalyst.

2. Results and discussion Fluoroalkylazides were synthesized by the reaction of the corresponding fluoroalkyl mesylates with sodium azide in DMSO with 18-crown-6 ether as catalyst in moderate to good yields (Scheme 1, Table 1). It was found that products (1) were very stable(up to 200 8C) and can be purified by distillation under atmospheric pressure. The fluoroalkyl tosylates can also be used in the same reaction, but the yield is not so good as that of mesylates.

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Scheme 1. Preparation 1,1-dihydrofluoroalkylazides.

Table 1 Result of the synthesis fluoroalkylazide Entry

Product

Yield (%)

1 2 3 4 5

1a 1b 1c 1d 1e

71 70 51 49 55

With the fluoroalkylazides in hand, we started the study on the 1,3-dipolar cycloaddition reaction of 1 with terminal alkynes. The reaction of 2,2,2-trifluoroethylazide 1a with phenylacetylene 2a was first carried out as a model reaction in order to optimize the reaction conditions (Table 2). When we used similar conditions as described by Sharpless [6], i.e. 1% mole copper (II) sulfate and 5 mol% sodium ascorbate, after stirring for 20 h at room temperature, the isolated yield of fluoroalkyled [1,2,3]-triazole was very poor (5%, see Table 2, Entry 1). If isobutanol was substituted by ethanol, isopropanol and acetonitile, respectively, the result was almost the same as that for isobutanol (Entries 2, 3, 4). When the solvent was changed to water, the yield was improved slightly, but even if the reaction temperature was raised to 80 8C, the yield was still disappointing, (23% yield; Entries 5, 6, 7). It means that Cu(I) reduced in situ cannot act as an effective catalyst in this reaction. However when CuI was used as a catalyst directly, acetonitrile and water (1:2, v/v) as a combined solvent, in addition to the presence of triethylamine, the yield can be raised to 58% (Entry 8). If CuI was purified before use, even better result can be obtained (67% yield, Entry 9). Entry 10 showed that triethylamine is necessary for the reaction, otherwise the yield decreased dramatically. The catalyst CuI was shown to be essential to the reaction, a control experiment indicated, without CuI, only a trace of the production (<10%) was obtained with a mixture of 1,4and 1,5-disubstituted regioisomer which can be separated by chromatography. The catalytic efficiency of CuI is very high, so that, 1 mol% is sufficient. It was found that if the substrate contains hydroxyl groups (e.g. propargyl alcohol), this reaction was interfered. However after protecting hydroxyl group with acetate or ketal, the reaction was smooth.

Scheme 2. NOSEY spectra of product 3aa.

It was interesting to note that for internal alkynes, no reaction was observed under similar conditions. The structure of product 3aa was confirmed both by the result of NOSEY spectra (Scheme 2) and an X-ray diffraction study (Scheme 3). Strong NOE effects have been observed between the proton of triazole’s ring and the CH2 proton in fluoroalkyl group in 3aa, suggesting that the triazole proton and N-substituent are in close proximity as in the 1,4-disubstituted triazole. Furthermore the X-ray crystal structure of 3aa indicated that it was an orthorhombic crystal with 1,4-disubutitution being confirmed.1 By this method other fluoroalkyltriazoles were synthesized in a similar manner (Scheme 4), no 1,5-disubstituted isomer was found in these reactions. The results are summarized in Table 3. Under the same conditions, when propiolic ester was used as the substrate, it was found that the mixture turned black immediately. After stirring for 24 h at room temperature, the desired product 1,2,3-triazole could not be obtained at all. This may be due to the reaction of triethyl amine with 1 The crystal data of 3aa has been deposited at the Cambridge Crystallographic Data Center and allocated the deposition number is CCDC 211220. Crystal data for 3aa: crystal system: orthorhombic; space group: Pca2(1); unit cell dimension: a ¼ 16:5536(16) A˚, b ¼ 5:5531(5) A˚, c ¼ 22:371(2) A˚, a ¼ 908, b ¼ 908, g ¼ 908; volume: 2056.4(3) A˚3; Z, calculated density: 8, 1.468 mg/m3; absorption coefficient: 0.130 mm3; F(0 0 0): 928; crystal size: 0:407 mm  0:109 mm  0:035 mm; theta range for data collection: 1.82–28.328; completeness to theta ¼ 28.32, 96.2%; data/restraints/ parameters: 4451/1/354; goodness-of-fit on F2: 0.795; final R indices [I > 2sigma910]: R1 ¼ 0:0485, wR2 ¼ 0:0842; R indices (all data ): R1 ¼ 0:1224, wR2 ¼ 0:1012; extinction coefficient: 0.0000(3); largest diff. Peak and hole: 0.178 and 0.181 A˚3.

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Table 2 Conditional test of the reaction of 1a with alkyne 2a Entry

Conditions t

CuSO45H2O; sodium ascorbate; BuOH: H2O ¼ 1:2; 20 h CuSO45H2O; sodium ascorbate; EtOH:H2O ¼ 1:2; 20 h CuSO45H2O; sodium ascorbate; i PrOH:H2O ¼ 1:2; 20 h CuSO45H2O; sodium ascorbate; CH3CN:H2O ¼ 1:2; 20 h CuSO45H2O; ascorbic acid; H2O; 20 h CuSO45H2O; ascorbic acid; H2O; 20 h CuSO45H2O; ascorbic acid; H2O; 20 h CuI; Et3N: CH3CN:H2O ¼ 1:2; 20 h CuI; (purified); Et3N; CH3CN:H2O ¼ 1:2; 20 h CuI; (purified); CH3CN:H2O ¼ 1:2; 20 h

1 2 3 4 5 6 7 8 9 10 a

Temperature (8C)

Yield (%)

25 25 25 25 25 50 80 25

5 2 13 Xa 21 27 23 58

25

48

No reaction.

Scheme 3. X-ray crystal structure of product 3aa.

Scheme 5. The reaction of propiolic esters.

Scheme 4. The 1,3-dipolar reaction of fluoroalkylazides.

propiolic ester in aqueous phase [11]. If triethyl amine was not added in the reaction system, the reaction could go smoothly. After stirring at room temperature for 20 h, 1,2,3triazole was obtained in moderate to good yield. By the same way propiolic amide 4d could also give the same transformation. The results are listed in Scheme 5 and Table 4. It was interesting to note that, high selectivity of the two triple bonds was observed for propiolic ester 4b. If one

equivalent of azide was added, the triple bond of propiolic acid participated in the reaction. No product reacted with the triple bond of propargyl alcohol was detected. If two equivalents of azide was added, then both triple bonds in the substrate reacted with azide, bis-1,2,3-triazole 6 was formed (Scheme 6). This means that electron-withdrawing groups in the triple bond will increase its reactivity, which was in accord to [5]. As proposed by Sharpless [6], the reaction mechanism is suggested as the following, Cu(I) firstly inserted to the terminal alkyne, forming copper (I) acetylide I ( as expected, no reaction was observed for internal alkynes), then copper (I) acetylide I reacted with fluoroalkyl azide to form the final product (Scheme 7). Because of the existence of copper (I) acetylide I, the reaction was regiospecific that only 1,4disubstituted 1,2,3-triazole was formed. In conclusion, we have been successful in developing a general method for the synthesis of fluoroalkyled 1,4-disubstituted 1,2,3-triazole by a regioselective 1,3-dipolar cycloaddition of terminal alkynes with fluoroalkylazides

Scheme 6. The formation of bis-1,2,3-triazole.

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Table 3 The results of the 1,3-dipolar reaction of fluoroalkylazides Entry

Azide

Alkyne

Product

Yield %*

1

CF3CH2N3

67

2

CF3CH2N3

65

3

CF3CH2N3

51

4

CF3CH2N3

52

5

CF3CH2N3

30

6

HCF2CF2CH2N3

82

7

HCF2CF2CH2N3

57

8

HCF2CF2CH2N3

78

9

HCF2CF2CH2N3

85

10

HCF2CF2CH2N3

44

11

CF3(CF2)5CH2N3

66

12

CF3(CF2)5CH2N3

65

13

CF3(CF2)5CH2N3

77

14

CF3(CF2)5CH2N3

90

15

CF3(CF2)5CH2N3

76

*

Isolated yields.

Y.-M. Wu et al. / Journal of Fluorine Chemistry 125 (2004) 1415–1423

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Table 4 The reaction of propiolic esters with fluoroalkyl azides Entry

Azides

Alkyne

Product

Yield %

1

CF3CH2N3

58

2

CF3CH2N3

42

3

CF3CH2N3

69

4

CF3CH2N3

49

5

HCF2CF2CH2N3

59

6

HCF2CF2CH2N3

61

7

HCF2CF2CH2N3

86

8

HCF2CF2CH2N3

73

9

CF3(CF2)5CH2N3

37

10

CF3(CF2)5CH2N3

62

11

CF3(CF2)5CH2N3

75

12

CF3(CF2)5CH2N3

17

catalyzed by Cu(I) salt in moderate to good yield. These compounds may find wide use in medicinal chemistry. Further studies on this reaction and its application in organic synthesis are in progress.

3. Experimental section General: Melting points and boiling points are uncorrected. IR spectra were obtained with a Perkin-Elmer 983G

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Scheme 7. Mechanism of 1,3-dipolar reaction catalyzed with Cu(I) salt.

spectrometer on KBr disks. NMR spectra were recorded either on a Varian-360L or Bruker AM-300 spectrometer with CDCl3 as solvent. Chemical shifts were reported in parts per million relative to TMS as an external standard (TMS ¼ 0) for 1 H NMR spectra and CFCl3 as an internal standard [ðCFCl3 Þ ¼ 0] for 19 F NMR (upfield shift being designated as negative) spectra. Coupling constants are given in Hertz (Hz). Low- and high- resolution mass spectra were recorded on a Hewlett-Packard HP-5989A and a Finnigan MAT spectrometer, respectively. Elemental analyses were performed at this institute. X-ray crystal diffraction was performed by SMART APEX CCD diffractometer and the analysis soft wear was Shelxl-97. Fluoroalkyl mesylate was prepared by the reported method [12]. 3.1. General procedure for the preparation of fluoroalkyl azide 1 To a 250 ml round bottle, HCF2CF2CH2OMs (21 g, 0.1 mol), NaN3 (9.8 g, 0.15 mol), 18-C-6 (0.5 g) and DMSO 100 ml were added successively. Then the mixture was stirred at 110 8C, monitored by 19 F NMR, till the peak of starting material disappeared (ca. 20 h). The mixture was cool down to 50 8C, poured into 200 ml ice water, extracted with ether (3  80 ml). The combined organic layer was washed with saturated brine (2  100 ml) and dried by magnesium sulfate, after removal of the solvent, the product was purified by distillation under atmospheric or reduced pressure. 2,2,2-Trifluoroethyl azide (1a) [13]: Colorless liquid; bp 54–55 8C. 1 H NMR: d 3.68 (q, J ¼ 8 Hz, 2H). 19 F NMR: d 72.12 (3F). 2,2,3,3-Tetrafluoropropanyl azide (1b): Colorless liquid; bp 81–82 8C. 1 H NMR: d 3.71 (t, J ¼ 14 Hz, 2H), 5.90 (tt, J1 ¼ 4 Hz, J2 ¼ 53 Hz, 1H). 19 F NMR: d 137.39 (d, 2F), 121.15–121.04 (m, 2F). IR(naet): 1110, 2117 cm1. MS m/z: 158 (Mþ, 6), 130 (2), 101 (47), 51 (100). Anal. Calcd for C3H3F4N3: C, 22.94; H, 1.93; N, 26.75; F, 48.38. Found: C, 22.77; H, 1.90; N, 26.37; F, 48.44. 1H,1H-perfluoroheptanyl azide (1c) [14]: Colorless liquid; bp 72–74 8C/36 mmHg. 1 H NMR: d 3.79 (t,

J ¼ 14 Hz, 2H). 19 F NMR: d 126.49 (s, 2F), 123.50 (s, 2F), 123.18 (s, 2F), 122.38 (s, 2F), 117.81 (t, 2F), 81.14 (3F). 5-chloro-2,2,3,3,4,4,5,5-Octafluoropentanyl azide (1d): Colorless liquid; bp 65–66 8C/25 mmHg. 1 H NMR: d 3.78 (t, J ¼ 14 Hz, 2H). 19 F NMR: d –122.99 (2F), 120.46 (2F), 117.94 (2F), 68.47 (2F). IR(naet): 1136, 1192, 1308, 2115 cm1. MS m/z: 291 (Mþ), 246, 131, 100, 69. Anal. Calcd for C5H2ClF8N3: C, 20.60; H, 0.69; N, 14.45; F, 52.13. Found: C, 20.77; H, 0.60; N, 14.38; F, 53.96. 1H,1H-perfluorononanyl azide (1e): Colorless liquid; bp 106 8C/30 mmHg. 1 H NMR: d 3.78 (t, J ¼ 14 Hz, 2H). 19 F NMR: d –126.58 (2F), 123.52 (2F), 123.12 (2F), 122.28 (6F), 117.88 (2F), 81.23 (2F). 3.2. Typical procedure for the reaction of fluoroalkyl azide with terminal alkyne To a 25 ml three-necked round flask, fluoroalkylazide (3 mmol), and terminal alkyne (3.3 mmol), triethylamine (3.3 mmol), acetonitrile (4 ml), water (8 ml) and CuI (6 mg, 0.03 mmol) were added successively. The mixture was stirred at r.t. for 20 h. Then 10 ml water was added, the mixture was extracted with ether (3  10 ml), the combined organic layer was washed with saturated brine and dried with sodium sulfate. After removal of solvent, the crude product was purified by flash chromatography on a silicon gel column with hexane/ethyl acetate (v/v: 5:1) as eluent. 4-Phenyl-1-(2,2,2-trifluoro-ethyl)-1H-[1,2,3]triazole (3aa): White solid; mp 158–159 8C. 1 H NMR: d 5.05 (q, J ¼ 8 Hz, 2H), 7.36–7.51 (m, 3H), 7.84–7.90 (m, 2H), 7.93 (s, 1H). 19 F NMR: d 71.38 (t, J ¼ 8 Hz, 3F). IR(KBr): 1397, 3132 cm1. MS m/z: 227 (Mþ, 31), 199 (16), 116 (100), 89 (25). Anal. Calcd for C10H8F3N3: C, 52.87; H, 3.55; N, 18.50; F, 25.09. Found: C, 52.91; H, 3.60; N, 18.85; F, 25.06. 4-Butyl-1-(2,2,2-trifluoro-ethyl)-1H-[1,2,3]triazole (3ab): White solid; mp 54–55 8C. 1 H NMR: d 0.95 (t, J ¼ 8 Hz, 3H), 1.33–1.47 (m, 2H), 1.61–1.75 (m, 2H), 2.76 (t, J ¼ 8 Hz, 2H), 4.95 (q, J ¼ 8 Hz, 2H), 7.44 (s, 1H). 19 F NMR: d 71.56 (3F); IR(KBr): 1180, 1558, 3077 cm1. MS m/z: 207 (Mþ, 6), 150 (20), 136 (100), 83 (52). Anal. Calcd for C8H12F3N3: C, 46.37; H, 5.84; N, 20.28; F, 27.51. Found: C, 46.41; H, 5.81; N, 20.31; F, 27.60. 4-Hexyl-1-(2,2,2-trifluoro-ethyl)-1H-[1,2,3]triazole (3ac): White solid; mp 57–58 8C. 1 H NMR: d 0.89 (t, J ¼ 7 Hz, 3H), 1.27–1.42 (m, 6H), 1.64–1.75 (m, 2H), 2.75 (t, J ¼ 8 Hz, 2H), 4.95 (q, J ¼ 8 Hz, 2H), 7.44 (s, 1H). 19 F NMR: d 71.54 (t, J ¼ 9 Hz, 3F). IR(KBr): 1268, 2929, 3075 cm1. MS m/z: 235 (Mþ, 3), 178 (25), 164 (100), 150 (20), 136 (48). Anal. Calcd for C10H16F3N3: C, 51.06; H, 6.86; N, 17.86; F, 24.23. Found: C, 51.18; H, 6.88; N, 17.76; F, 24.18. 4-(Tetrahydro-pyran-2-yloxymethyl)-1-(2,2,2-trifluoroethyl)-1H-[1,2,3]triazole (3ad): White solid; mp 120–

Y.-M. Wu et al. / Journal of Fluorine Chemistry 125 (2004) 1415–1423

121 8C. 1 H NMR: d 1.50–1.92 (m, 6H), 3.53–3.85 (m, 2H), 4.69 (d, J ¼ 12 Hz, 1H), 4.77 (t, J ¼ 4 Hz, 1H), 4.92 (d, J ¼ 13 Hz, 1H), 4.987 (q, J ¼ 8 Hz, 2H), 7.72 (s, 1H). 19 F NMR: d 71.45 (t, J ¼ 6 Hz, 3F). IR(KBr): 1566, 2973 cm1. MS m/z: 265 (Mþ, 2), 165 (81), 136 (100), 110 (22), 85(36). Anal. Calcd for C10H14F3N3O2: C, 45.28; H, 5.32; N, 15.84; F, 21.49; O, 12.06. Found: C, 45.19; H, 5.26; N, 15.86; F, 21.83. 1-(2,2,2-Trifluoro-ethyl)-4-acetyloxymethyl-1H-[1,2,3]triazol (3ae): Colorless liquid. 1 H NMR: d 2.07 (s, 3H), 5.50 (q, J ¼ 8 Hz, 2H), 5.22 (s, 2H), 7.80 (s, 1H). 19 F NMR: d 71.52 (t, J ¼ 8 Hz, 3F). IR(neat): 1244, 1745, 2977, 3150 cm1. MS m/z: 224 (Mþþ1, 1), 153 (15), 83 (14), 43 (100). Anal. Calcd for C7H8F3N3O2: C, 37.68; H, 3.61; N, 18.83; F, 25.54. Found: C, 37.58; H, 3.40; N, 19.20; F, 25.58. 4-Phenyl-1-(2,2,3,3-tetrafluoro-propyl)-1H-[1,2,3]triazole (3ba): White solid; mp 143–144 8C. 1 H NMR: d 5.01 (t, J ¼ 8 Hz, 2H), 5.94 (tt, J1 ¼ 2 Hz, J2 ¼ 53 Hz, 1H) 7.35– 7.50 (m, 3H), 7.84–7.89 (m, 2H), 7.93 (s, 1H). 19 F NMR: d 136.29 (d, J ¼ 54 Hz, 2F), 119.80 (t, J ¼ 14 Hz, 2F). IR(KBr): 1465, 3131 cm1. MS m/z: 259 (Mþ, 17), 231 (41), 116 (100), 89 (25). Anal. Calcd for C11H9F4N3: C, 50.97; H, 3.50; N, 16.21; F, 29.32. Found: C, 50.81; H, 3.39; N, 16.05; F, 29.32. 4-Butyl-1-(2,2,3,3-tetrafluoro-propyl)-1H-[1,2,3]triazole (3bb): Colorless liquid. 1 H NMR: d 0.93 (t, J ¼ 7 Hz, 3H), 1.32–1.45 (m, 2H), 1.61–1.73 (m, 2H), 2.74 (t, J ¼ 8 Hz, 2H), 4.90 (tt, J1 ¼ 2 Hz, J2 ¼ 14 Hz, 2H), 5.88 (tt, J1 ¼ 3 Hz, J2 ¼ 53 Hz, 1H), 7.43 (s, 1H). 19 F NMR: d 136.79 (d, J ¼ 57 Hz, 2F), 120.32 (t, J ¼ 14 Hz, 2F). IR(neat): 1111, 1557, 2963 cm1. MS m/z: 239 (Mþ, 6). HRMS (EI) calcd. for C9H13F4N3: 239.10456, found: 239.10554. 4-Hexyl-1-(2,2,3,3-tetrafluoro-propyl)-1H-[1,2,3]triazole (3bc): White solid; mp 40–41 8C. 1 H NMR: d 0.89 (t, J ¼ 7 Hz, 3H), 1.25–1.44 (m, 6H), 1.64–1.78 (m, 2H), 2.74 (t, J ¼ 8 Hz, 2H), 4.91 (t, J ¼ 14 Hz, 2H), 5.88 (tt, J1 ¼ 3 Hz, J2 ¼ 53 Hz, 1H), 7.43 (s, 1H). 19 F NMR: d 136.74 (d, J ¼ 49 Hz, 2F), 120.25 (t, J ¼ 15 Hz, 2F). IR(KBr): 1113, 1562, 2930 cm1. MS m/z: 267 (Mþ, 7), 210 (35), 196 (100), 168 (62). Anal. Calcd for C11H17F4N3: C, 49.43; H, 6.41; N, 15.72; F, 28.43. Found: C, 49.24; H, 6.17; N, 15.74. 1-(2,2,3,3-Tetrafluoro-propyl)-4-(tetrahydro-pyran-2-yloxymethyl)-1H-[1,2,3]triazole (3bd): White solid; mp 64– 65 8C. 1 H NMR: d 1.48–1.89 (m, 6H), 3.71–3.96 (m, 2H), 4.68 (d, J ¼ 13 Hz, 1H), 4.75 (s, 1H), 4.90 (d, J ¼ 13 Hz, 1H), 4.94 (t, J ¼ 14 Hz, 2H), 7.71 (s, 1H). 19 F NMR: d 136.50 (d, J ¼ 53 Hz, 2F), 120.01 (t, J ¼ 15 Hz, 2F). IR(KBr): 1567, 2962 cm1. MS m/z: 297 (Mþ, 1), 197 (62), 168 (100), 142 (18), 85 (47). Anal. Calcd for C11H15F4N3O2: C, 44.45; H, 5.09; N, 14.14; F, 25.57; O, 10.76. Found: C, 44.24; H, 5.28; N, 14.16; F, 25.78. 1-(2,2,3,3-Ttetrafluoro-propyl)-4-acetyloxymethyl-1H-[1, 2,3]triazole (3be): Colorless liquid. 1 H NMR: d 2.06 (s, 3H), 4.95 (tt, J1 ¼ 1 Hz, J2 ¼ 14 Hz, 2H), 5.21(s, 2H), 5.91 (tt,

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J1 ¼ 3 Hz, J2 ¼ 53 Hz, 1H), 7.78 (s, 1H). 19 F NMR: d 136.45 (d, J ¼ 53 Hz, 2F), 120.01 (t, J ¼ 12 Hz, 2F). IR(neat): 1241, 1744, 3152 cm1. MS m/z: 255 (Mþ, 1), 212 (7), 185 (68), 168 (62), 43 (100). Anal. Calcd for C8H9F4N3O2: C, 37.66; H, 3.56; N, 16.47; F, 29.78; O, 12.54. Found: C, 37.70; H, 3.78; N, 16.56; F, 29.74. 4-Phenyl-1-(2,2,3,3,4,4,5,5,6,6,7,7,7-tridecafluoro-heptyl)-1H-[1,2,3]triazole (3ca): White solid; mp 129–130 8C. 1 H NMR: d 5.12 (t, J ¼ 15 Hz, 2H), 7.35–7.52 (m, 3H), 7.84–7.89 (m, 2H), 7.93 (s, 1H). 19 F NMR: d 126.35 (s, 2F), 123.12 (s, 4F), 122.06 (s, 2F), 117.00 (t, J ¼ 14 Hz, 2F), 81.00 (t, J ¼ 6 Hz, 3F). IR(KBr): 1466, 3092 cm1. MS m/z: 477 (Mþ, 3), 449 (22), 116 (100), 89 (25), 69 (26). Anal. Calcd for C15H8F13N3: C, 37.75; H, 1.69; N, 8.81; F, 51.75. Found: C, 37.77; H, 1.90; N, 8.79; F, 52.08. 4-Butyl-1-(2,2,3,3,4,4,5,5,6,6,7,7,7-tridecafluoro-heptyl)1H-[1,2,3]triazole (3cb): White solid; mp 88–89 8C. 1 H NMR: d 0.95 (t, J ¼ 8 Hz, 3H), 1.33–1.47 (m, 2H), 1.63– 1.75 (m, 2H), 2.77 (t, J ¼ 8 Hz, 2H), 5.03 (t, J ¼ 15 Hz, 2H), 7.45 (s, 1H). 19 F NMR: d 126.40 (2F), 123.29 (2F), 123.10 (2F), 122.10 (2F), 117.16 (2F), 81.10 (3F). IR(KBr): 1185, 1557, 2961 cm1. MS m/z: 457 (Mþ, 3), 438 (12), 414 (69), 400 (19), 386 (98), 110 (100). Anal. Calcd for C13H12F13N3: C, 34.15; H, 2.65; N, 9.19; F, 54.02. Found: C, 34.21; H, 2.74; N, 9.32; F, 54.07. 4-Hexyl-1-(2,2,3,3,4,4,5,5,6,6,7,7,7-tridecafluoro-heptyl)-1H-[1,2,3]triazole (3cc): White solid; mp 85–86 8C. 1 H NMR: d 0.89 (t, J ¼ 7 Hz, 3H), 1.26–1.43 (m, 6H), 1.64– 1.76 (m, 2H), 2.76 (t, J ¼ 8 Hz, 2H), 5.03 (t, J ¼ 14 Hz, 2H), 7.45 (s, 1H). 19 F NMR: d 126.36 (2F), 123.27 (2F), 123.07 (2F), 122.10 (2F), 117.12 (2F), 81.02 (3F). IR(KBr): 1235, 2932 cm1. MS m/z: 485 (Mþ, 5), 466 (10), 442 (16), 428 (37), 414 (100), 400 (17), 386 (48). Anal. Calcd for C15H16F13N3: C, 37.13; H, 3.32; N, 8.66; F, 50.89. Found: C, 37.19; H, 3.34; N, 8.74; F, 51.27. 4-(Tetrahydro-pyran-2-yloxymethyl)-1-(2,2,3,3,4,4,5,5,6,6, 7,7,7-tridecafluoro-heptyl)-1H-[1,2,3]triazole (3cd): White solid; mp 72–73 8C. 1 H NMR: d 1.48–1.91 (m, 6H), 3.54– 3.95 (m, 2H), 4.70 (d, J ¼ 13 Hz, 1H), 4.75 (t, J ¼ 3 Hz, 1H), 4.91 (d, J ¼ 13 Hz, 1H), 5.06 (t, J ¼ 15 Hz, 2H), 7.73 (s, 1H). 19 F NMR: d 126.45 (2F), 123.20 (4F), 122.12 (2F), 117.18 (2F), 81.09 (3F). IR(KBr): 1456, 2944 cm1. MS m/z: 515 (Mþ, 2), 415 (43), 386 (100), 360 (14), 85 (56). Anal. Calcd for C15H14F13N3O2: C, 34.96; H, 2.74; N, 8.15; F, 47.93; O, 6.21. Found: C, 34.89; H, 2.89; N, 8.12; F, 48.21. 1-(2,2,3,3,4,4,5,5,6,6,7,7,7-Tridecafluoro-heptyl)-4-acetyloxymethyl-1H-[1,2,3]triazole (3ce): White solid; mp 60– 61 8C. 1 H NMR: d 2.10 (s, 3H), 5.07 (t, J ¼ 15 Hz, 2H), 5.26 (s, 2H), 7.80 (s, 1H). 19 F NMR: d –126.40 (2F), 123.10 (4F), 122.09 (2F), 117.10 (2F), 81.05 (3F). IR(KBr): 1244, 1735, 3138 cm1. MS m/z: 473 (Mþ, 1), 454 (5), 403 (38), 386 (24), 43 (100). Anal. Calcd for C12H8F13N3O2: C, 30.46; H, 1.70; N, 8.88; F, 52.19; O, 6.76. Found: C, 30.46; H, 1.79; N, 8.89; F, 52.54.

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3.3. Typical procedure for the reaction of fluoroalkyl azide with derivatives of propiolic acid To a 25 ml 3-necked round flask, fluoroalkylazide (3 mmol), and propiolic ester (amide) (3.3 mmol), acetonitrile (4 ml), water (8 ml) and CuI (6 mg, 0.03 mmol) were added successively. The mixture was stirred at r.t. for 20 h. Then 10 ml water was added, the mixture was extracted with ether (3  10 ml). The combined organic layer was washed with saturated brine and dried with sodium sulfate. After removal of solvent under reduced pressure, the crude product was purified by flash chromatography on a silicon gel column with hexane/ethyl acetate (v/v: 5:1) as eluent. Methyl-1-(2,2,2-trifluoro-ethyl)-1H-[1,2,3]triazole-4carboxylic ester (5aa): White solid; mp 107–108 8C. 1 H NMR: d 3.95 (s, 3H), 5.09 (q, J ¼ 8 Hz, 2H), 8.29 (s, 1H). 19 F NMR: d –76.33 (t, J ¼ 8 Hz, 3F). IR(KBr): 1235, 1548, 1721, 3135 cm1. MS m/z: 209 (Mþ, 2), 178 (28), 151 (86), 110 (100), 83 (69). Anal. Calcd for C6H6F3N3O2: C, 34.46; H, 2.89; N, 20.09; F, 27.25. Found: C, 34.40; H, 2.99; N, 20.27; F, 27.44. 2-propynyl-1-(2,2,2-trifluoro-ethyl)-1H-[1,2,3]triazole4-carboxylic ester (5ab): White solid; mp 95–96 8C. 1 H NMR: d 2.55 (t, J ¼ 2 Hz, 1H), 4.97 (d, J ¼ 8 Hz, 2H), 5.10 (q, J ¼ 8 Hz, 2H), 8.34 (s, 1H). 19 F NMR: d –71.35 (t, J ¼ 8 Hz, 3F). IR(KBr): 1054, 1091, 1178, 1212, 1356, 1583, 1729, 3121, 3309 cm1. MS m/z: 233 (Mþ, 1), 204 (29), 160 (31), 110 (100), 83 (76). Anal. Calcd for C8H6F3N3O2: C, 41.21; H, 2.59; N, 18.02; F, 24.45. Found: C, 41.36; H, 2.52; N, 18.19; F, 24.54. Allyl-1-(2,2,2-trifluoro-ethyl)-1H-[1,2,3]triazole-4-carboxylic ester (5ac): White solid; mp 91–92 8C. 1 H NMR: d 4.84–4.90 (m, 2H), 5.09 (q, J ¼ 8 Hz, 2H), 5.28–5.47 (m, 2H), 5.96–6.10 (m, 2H), 8.30 (s, 1H). 19 F NMR: d –71.39 (t, J ¼ 8 Hz, 3F). IR(KBr): 1178, 1218, 1398, 1728, 3030, 3122 cm1. MS m/z: 235 (Mþ, 2), 179 (83), 151 (61), 110 (100), 83 (36). Anal. Calcd for C8H8F3N3O2: C, 40.86; H, 3.43; N, 17.87. Found: C, 40.90; H, 3.40; N, 17.97. Allyl-1-(2,2,2-trifluoro-ethyl)-1H-[1,2,3]triazole-4-carboxylic amide (5ad): White solid; mp 172–173 8C. 1 H NMR: d 4.10 (t, J ¼ 5 Hz, 2H), 5.05 (q, J ¼ 8 Hz, 2H), 5.18–5.32 (m, 2H), 5.86–5.99 (m, 1H), 8.29 (s, 1H). 19 F NMR: d –68.43 (t, J ¼ 8 Hz, 3F). IR(KBr): 1099, 1180, 1243, 1268, 1314, 1526, 1585, 1647, 3080, 3120, 3317 cm1. MS m/z: 234 (Mþ, 23), 219 (27), 205 (71), 110 (100), 83 (61). Anal. Calcd for C8H9F3N4O: C, 41.03; H, 3.87; N, 23.92; F, 24.34. Found: C, 41.16; H, 3.89; N, 23.93; F, 24.42. Methyl-1-(2,2,3,3-tetrafluoro-propyl)-1H-[1,2,3]triazole4-carboxylic ester (5ba): White solid; mp 89–90 8C. 1 H NMR: d 3.93 (s, 3H), 5.04 (t, J ¼ 14 Hz, 2H), 5.96 (tt, J1 ¼ 3 Hz, J2 ¼ 53 Hz, 1H), 8.28 (s, 1H). 19 F NMR: d – 140.83 (d, J ¼ 53 Hz, 2F), 124.54 (t, J ¼ 14 Hz, 2F). IR(KBr): 1225, 1444, 1734, 3109 cm1. MS m/z: 241 (Mþ, 2), 222 (4), 210 (29), 142 (98), 51 (100). Anal. Calcd for C7H7F4N3O2: C, 34.87; H, 2.93; N, 17.43; F, 31.51. Found: C, 34.76; H, 3.00; N, 17.51; F, 31.60.

2-Propynyl-1-(2,2,3,3-tetrafluoro-propyl)-1H-[1,2,3]triazole-4-carboxylic ester (5bb): White solid; mp 72–73 8C. 1 H NMR: d 2.54 (t, J ¼ 2 Hz, 1H), 4.97 (d, J ¼ 2 Hz, 2H), 5.06 (t, J ¼ 14 Hz, 2H), 5.97 (tt, J1 ¼ 3 Hz, J2 ¼ 53 Hz, 1H), 8.32 (s, 1H). 19 F NMR: d –135.73 (d, J ¼ 53 Hz, 2F), 119.37 (t, J ¼ 14 Hz, 2F). IR(KBr): 1206, 1536, 1733, 2139, 3111, 3308 cm1. MS m/z: 265 (Mþ, 1), 236 (12), 192 (21), 142 (52), 51 (100). Anal. Calcd for C9H7F4N3O2: C, 40.77; H, 2.66; N, 15.85; F, 28.66. Found: C, 40.82; H, 2.66; N, 15.99; F, 29.01. Allyl-1-(2,2,3,3-tetrafluoro-propyl)-1H-[1,2,3]triazole-4carboxylic ester (5bc): White solid; mp 76–77 8C. 1 H NMR: d 4.85–4.88 (m, 2H), 5.04 (t, J ¼ 14 Hz, 2H), 5.29–5.46 (m, 2H), 5.94–6.14 (m, 2H), 8.28 (s, 1H). 19 F NMR: d –135.86 (d, J ¼ 54 Hz, 2F), 119.49 (t, J ¼ 13 Hz, 2F). IR(KBr): 1207, 1536, 1729, 3109, 3308 cm1. MS m/z: 267 (Mþ, 3), 248 (2), 211 (32), 142 (100), 41 (78). Anal. Calcd for C9H9F4N3O2: C, 40.46; H, 3.40; N, 15.73; F, 28.44. Found: C, 40.60; H, 3.46; N, 15.99; F, 28.76. Allyl1-(2,2,3,3-tetrafluoro-propyl)-1H-[1,2,3]triazole4-carboxylic amide (5bd): White solid; mp 140–141 8C. 1 H NMR: d 4.12–4.17 (m, 2H), 5.04 (t, J ¼ 14 Hz, 2H), 5.22–5.37 (m, 2H), 5.78–6.15 (m, 2H), 8.29 (s, 1H). 19 F NMR: d –135.81 (d, J ¼ 53 Hz, 2F), 119.26 (t, J ¼ 14 Hz, 2F). IR(KBr): 1114, 1528, 1651, 3331 cm1. MS m/z: 266 (Mþ, 32), 251 (50), 237 (69), 142 (100), 51 (75). Anal. Calcd for C9H10F4N4O: C, 40.61; H, 3.79; N, 21.05; F, 28.55. Found: C, 40.76; H, 3.41; N, 20.97; F, 28.59. Methyl-1-(2,2,3,3,4,4,5,5,6,6,7,7,7-tridecafluoro-heptyl)1H-[1,2,3]triazole-4-carboxylic ester (5ca): White solid; mp 132–133 8C. 1 H NMR: d 4.00 (s, 3H), 5.15 (t, J ¼ 15 Hz, 2H), 8.30 (s, 1H). 19 F NMR: d –126.37 (2F), 123.08 (4F), 122.03 (2F), 116.98 (2F), 80.99 (3F). IR(KBr): 1217, 1731, 3107 cm1. MS m/z: 460 (Mþþ1, 2), 440 (9), 360 (33), 112 (53), 69 (100). Anal. Calcd for C11H6F13N3O2: C, 28.77; H, 1.32; N, 9.15; F, 53.79. Found: C, 28.66; H, 1.47; N, 9.33; F, 53.96. 2-Propynyl-1-(2,2,3,3,4,4,5,5,6,6,7,7,7-tridecafluoroheptyl)-1H-[1,2,3]triazole-4-carboxylic ester (5cb): White solid; mp 87–88 8C. 1 H NMR: d 2.56 (t, J ¼ 2 Hz, 1H), 4.99 (d, J ¼ 2 Hz, 2H), 5.15 (t, J ¼ 14 Hz, 2H), 8.33 (s, 1H). 19 F NMR: d –126.33 (2F), 123.03 (4F), 122.01 (2F), 116.93 (2F), 80.97 (3F). IR(KBr): 1242, 1373, 1549, 1728, 3279 cm1. MS m/z: 483 (Mþ, 9), 464 (12), 410 (23), 360 (65), 69 (100). Anal. Calcd for C13H6F13IN3O2: C, 32.32; H, 1.25; N, 8.70; F, 51.11. Found: C, 32.19; H, 1.52; N, 8.70; F, 51.49. Allyl 1-(2,2,3,3,4,4,5,5,6,6,7,7,7-tridecafluoro-heptyl)1H-[1,2,3]triazole-4-carboxylic ester (5cc): White solid; mp 85–86 8C. 1 H NMR: d 4.87–4.91 (m, 2H), 5.15 (t, J ¼ 15 Hz, 2H), 5.31–5.36 (m, 2H), 5.98–6.10 (m, 1H), 8.30 (s, 1H). 19 F NMR: d –126.35 (2F), 123.05 (4F), 122.02 (2F), 116.95 (2F), 80.97 (3F). IR(KBr): 1247, 1374, 1727, 3126 cm1. MS m/z: 485 (Mþ, 2), 466 (5), 401 (29), 360 (49), 69 (56), 41 (100). Anal. Calcd for

Y.-M. Wu et al. / Journal of Fluorine Chemistry 125 (2004) 1415–1423

C13H8F13N3O2: C, 32.18; H, 1.66; N, 8.66; F, 50.90. Found: C, 32.10; H, 1.66; N, 8.67; F, 50.62. Allyl1-(2,2,3,3,4,4,5,5,6,6,7,7,7-tridecafluoro-heptyl)-1H[1,2,3]triazole-4-carboxylic amide (5cd): White solid. 1 H NMR: d 4.05 (t, J ¼ 6 Hz, 2H), 5.06–5.28 (m, 2H), 5.63 (t, J ¼ 15 Hz, 2H), 5.89–6.02 (m, 1H), 8.63 (s, 1H). 19 F NMR: d –127.01 (2F), 123.72 (4F), 122.71 (2F), 117.51 (2F), 81.94 (3F). IR(KBr): 1143, 1241, 1579, 1653, 2110, 2933, 3116, 3329 cm1. MS m/z: 484 (Mþ, 25), 455 (27), 360 (34), 137 (30), 56 (100). HRMS (ESI) calcd. for C13H9F13N4O: 484.05687, found: 484.05633. 3.4. preparation of bistriazole (6) As the procedure described in 3.3, but the mole ratio of fluoroalkyl azide with alkyne is 2:1. (6): White solid; mp 129–130 8C. 1 H NMR: d 5.29 (t, J ¼ 15 Hz, 2H), 5.5.14 (t, J ¼ 15 Hz, 2H), 5.49 (s, 2H), 6.28–6.70 (m, 2H), 8.26 (s, 1H), 8.73 (s, 1H). 19 F NMR: d 139.14–138.86 (m, 2F), 122.79–122.47 (m, 2F). IR(KBr): 1043, 1106, 1244, 1385, 1548, 1731, 3119 cm1. MS m/z: 422 (Mþ, 1), 394 (30), 352 (43), 168 (58), 142 (100), 51 (89). Anal. Calcd for C12H10F8N6O2: C, 34.14; H, 2.39; N, 19.90; F, 36.00. Found: C, 34.31; H, 2.42; N, 18.89; F, 36.08. Acknowledgements The authors thank the Shanghai Science and Technology Committee for part financial support. Project No.: 035211018.

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