Zinc promoted asymmetric propargylation of N-(2-chlorotetrafluoroethanesulfin)imines

Journal of Fluorine Chemistry 168 (2014) 44–49

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Zinc promoted asymmetric propargylation of N-(2-chlorotetrafluoroethanesulfin)imines Li-Juan Liu, Jin-Tao Liu * Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China

A R T I C L E I N F O

A B S T R A C T

Article history: Received 22 May 2014 Received in revised form 9 August 2014 Accepted 12 August 2014 Available online 23 August 2014

Zinc promoted asymmetric Barbier-type homopropargylation of aldimines is demonstrated. 2Chlorotetrafluoroethanesulfinamide was used as the chiral auxiliary and the corresponding homopropargylamines were obtained in good yields with up to 98% diastereoselectivity under mild conditions. ß 2014 Elsevier B.V. All rights reserved.

Keywords: 2-Chlorotetrafluoroethanesulfinimine Homopropargylamine Chiral auxiliary Asymmetric synthesis Fluorine

1. Introduction Homopropargylic amines represent the core of many pharmaceuticals [1] and constitute versatile precursors of nitrogencontaining building blocks [2]. Their racemic synthesis through the attack of nucleophiles to imines has been well developed [3]. However, only a few methods were reported for the efficient preparation of enantiomerically enriched homopropargylic amines [4,5], and their synthesis still remains a challenge. In 2008, the reaction of enantiomerically pure N-sulfinylimines with Grignard reagents was reported in the enantioselective synthesis of dihydroisoindol-4-ols [6]. However, only one example was given for the propargylic reaction, the addition of 1-propynylmagnesium bromide to (S)-tert-butanesulfinimine derived from 5-methyl furfural at 50 8C, which afforded the corresponding adduct in 70% yield with 95% de. Very recently, Yus and coworkers reported the Barbier-type reaction of chiral tert-butanesulfinimines with silylated propargyl bromides promoted by indium under sonication [7]. Good yields and diastereoselectivities were achieved, but the diastereoselectivities were poor when zinc was used instead of indium. It is well known that the Barbier-type synthesis involving the attack of propargyl zinc to imines is appealing for cheap materials and mild reaction conditions [2(b),8]. Up to now,

* Corresponding author. Tel.:+86 21 54925188. E-mail address: [email protected] (J.-T. Liu). http://dx.doi.org/10.1016/j.jfluchem.2014.08.008 0022-1139/ß 2014 Elsevier B.V. All rights reserved.

however, direct asymmetric addition of propargyl zinc to imines with both good diastereoselectivities and yields has not been reported. Herein, we report for the first time the Ti(Oi-Pr)4 and CuCl catalyzed diastereoselective homopropargylation of 2-chlorotetrafluoroethanesulfinimines with propargyl zinc. 2. Results and discussion Recently, a kind of practical fluorinated chiral auxiliary, polyfluoroalkanesulfinamide, was developed in our laboratory [9]. Like the tert-butanesulfinyl induced aminoallylation [10], zinc mediated one-pot aminoallylation of aldehyde was achieved successfully using (S)-2-chlorotetrafluoroethanesulfinamide (1) as the auxiliary (Scheme 1) [11]. The corresponding allylic amines 4 with a configuration of Ss, Sc were obtained in good yields with high diastereoselectivities. Due to the strong electron-withdrawing effect of fluoroalkanesulfinyl group, the reaction could take place at lower temperature. In addition, the presence of fluorine facilitated the detection of the reaction process and the diastereoselectivity by 19F NMR spectrum without working-up of the reaction mixture. Inspired by this result, we further tried the aminopropargylation of aldehydes following the procedure depicted in Scheme 1. In an initial trial, compound 1 was treated with 1.1 equiv of 4-chlorobenzaldehyde (2a) in the presence of zinc powder (2.0 equiv) and Ti(Oi-Pr)4 (1.5 equiv) in THF at room temperature.

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Scheme 1. One-pot aminoallylation of aldehydes.

Scheme 2. One-pot aminopropargylation of 2a.

After 1 disappeared, propargyl bromide (5a) was added and the reaction temperature was raised to 35 8C. Unfortunately, only imine 6a was obtained and no expected homopropargylic amine 7a was observed in 19F NMR spectrum (Scheme 2). Carrying out the reaction under reflux still failed to afford 7a. However, when imine 6a was isolated and treated with 5a (2.0 equiv) in the presence of 2.0 equiv of zinc and 0.2 equiv of Ti(Oi-Pr)4 at 35 8C in THF, a small amount of the desired product 7a was observed in 19F NMR spectrum. Raising the temperature to 50 8C, 7a (Ss, Sc) was obtained in 80% yield with a de of 80% as shown in 19F NMR spectrum (Table 1, entry 1). Further screening the reaction conditions showed that the addition of 0.1 equiv of CuCl could improve the yield of 7a to 90% without any erosion in diastereoselectivity (entry 2). Additionally, when the reaction was carried out without Ti(Oi-Pr)4, 7a was not detected and imine 6a was recovered.

Under the optimized conditions, the scope of imines 6 was investigated and the results are summarized in Table 1. The reaction tolerated a broad range of functional groups and the electronic effect of substituents has little influence on the reactivity of imines 6. Halide substituted imines 6c–6g reacted well with 5a to give the corresponding products 7c–7g in good yields with high diastereoselectivities (Table 1, entries 4-8). The use of a bromo substitution allows further modification of products 7. The reactions of electron-rich imines bearing methyl- (entry 9), phenyl- (entry 10), or methoxy-substitution (entry 12) proceeded well under the reaction conditions, although a slightly prolonged reaction time was required. Heteroaryl imines 6l and 6m (entries 13 and 14) reacted smoothly and afforded the corresponding products in good yields. Good yields were also achieved with imines derived from aliphatic aldedydes, although the diastereoselectivities were lower (entries 16–18). For imine 6q, products 7q

Table 1 2-Chlorotetrafluoroethanesulfinyl group induced homopropargylation of imines 6

.

Entry a

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 a b

Imine 6a 6a 6b 6c 6d 6e 6f 6g 6h 6i 6j 6k 6l 6m 6n 6o 6p 6q

R

Time (h)

p-ClC6H4 p-ClC6H4 C6H5 m-ClC6H4 o-ClC6H4 p-FC6H4 o-FC6H4 p-BrC6H4 p-MeC6H4 p-PhC6H4 p-CF3C6H4 p-MeOC6H4 2-Furyl 2-Thienyl t-Bu Cyclohexyl (CH3)2CH PhCH5 5CH(E)

The reaction was carried out without CuCl. Yields in brackets and de were determined by

19

F NMR spectra.

8 8 10 8 10 9 12 14 10 13 7 11 11 14 10 9 9 10

Product 7a 7a 7b 7c 7d 7e 7f 7g 7h 7i 7j 7k 7l 7m 6n 7o 7p 7q/7q0

Isolated yield (%) b

(80) 79(90)b 73 66 67 81 58 61 82 79 65 81 84 65 – 72 74 67/13

de (%)b 80 80 84 76 92 >96 >96 88 >98 >98 88 >98 >98 72 – 72 64 60

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L.-J. Liu, J.-T. Liu / Journal of Fluorine Chemistry 168 (2014) 44–49

Scheme 3. The reaction of 6r and 5a.

Scheme 4. Conversion of 7b to 9b.

and 7q0 were isolated as diastereomers (entry 18). In the case of 6n, the addition reaction did not occur because of the steric hindrance, and 62% of 6n was recovered after workup of the reaction mixture (entry 15). As a control experiment, imine 6r prepared from tertbutanesulfinamide and aldehyde 2a was treated with 5a under similar conditions, but no adduct was observed and 6r was all recovered (Scheme 3). In comparison with the result of entry 2 in Table 1, it revealed that the electrophilicity of the corresponding imines was obviously enhanced by the fluoroalkanesulfinyl group.

To determine the stereoselectivity of the product, 7b was subjected to deprotection and re-protection with Tosyl group in sequence (Scheme 4). As a result, 9b (>98% ee) was obtained in a total yield of 64%. Comparing the optical rotation of 9b with the reported value [4(b)] indicated that the configuration of the new generated chiral center in compound 7 was S. Taking imine 6a as an example, the scope of substituted propargylic bromides was investigated. The reactions of 6a with 5b, 5c or 5d were carried out under the optimal conditions and the results were summarized in Fig. 1. The expected

Fig. 1. The reaction of 6a with substituted propargylic bromides.

Scheme 5. The reaction of 5b under different conditions.

L.-J. Liu, J.-T. Liu / Journal of Fluorine Chemistry 168 (2014) 44–49

homopropargylic amine 7s was obtained in 79% yield with a de of 76% from 5b. For dimethyl substituted propargylic bromide 5d, the reaction took place at higher temperature (65 8C) due to the steric hindrance. As a result, the addition product 7u was obtained with a lower yield (60%) and de (68%). Surprisingly, the diene product 7t was obtained in 80% yield with up to 84% de when methyl substituted imine 5c was used as the substrate. It was mentioned in Scheme 2 that this homopropargylic reaction only applied to isolated imines 6. The one-pot aminopropargylation of aldehydes using 1 as the auxiliary did not work like the aminoallylation. The preliminary results indicated that it might be caused by the water produced during the formation of imines 6. As shown in Scheme 5, when water (1.0 equiv) was added to the reaction system of 6a and 5b under the standard conditions (Eq. (1)), no desired addition product was found and imine 6a remained unchanged. Instead, propa-1,2-dien-1-ylbenzene (10b) was isolated in 76% yield. Therefore, 10b should be derived from 5b under the reaction conditions. The result of control experiment confirmed that (Eq. (2)): when 5b was subjected to the same conditions in the absence of 6a, 10b was obtained in 80% yield. This explains why the one-pot aminopropargylation reaction could not occur. 3. Conclusions In summary, we have developed an efficient asymmetric homopropargylation of aldimines induced by 2-chlorotetrafluoroethanesulfinyl group. Good yields and excellent de were achieved for various imines under mild conditions. Further synthetic application of this reaction and the application of polyfluoroalkanesulfinamide in asymmetric synthesis are in progress in our laboratory. 4. Experimental 4.1. General remarks 1 H NMR spectra were recorded at 300 or 400 MHz using CDCl3 as the solvent and TMS as the internal standard. The data are reported as (s = singlet, d = doublet, m = multiplet, coupling constant in Hz, integration). 19F NMR spectra were recorded at 282 MHz, chemical shifts (d, 1H-decoupled) are reported in ppm using CFCl3 as internal standard. 13C NMR spectra were recorded with 1H-depoupling at 100 MHz and referenced to CDCl3 at 77.16 ppm. Flash chromatography was carried out on handpacked columns of silica gel (300–400 mesh). THF and CH2Cl2 were freshly distilled and all other commercially available reagents were used as received.

4.2. General procedure for homopropargylation of imines 6 To a mixture of imine 6 (1.0 mmol), zinc power (2.0 mmol) and THF (2.0 mL) was added CuCl (0.1 mmol), Ti(Oi-Pr)4 (0.2 mmol) and 5a (2.0 mmol). The resulting mixture was stirred at 50 8C and monitored by 19F NMR. After disappearance of 6, the mixture was cooled to room temperature and diluted with Et2O (10 mL). The resulting mixture was filtrated through celite and the solid was washed with Et2O (5 mL). The filtrate was concentrated under reduced pressure and purified by column chromatography (EA/PE: 1/30), giving product 7. 4.2.1. (4S,Ss)-N-(2-Chlorotetrafluoroethanesulfinyl)-4-(pchlorophenyl)but-1-yne-4-amine (7a) Colorless oil. FT-IR (film) 3306, 2925, 1599, 1495, 1262, 1176, 908, 797, 650 cm1. 1H NMR (CDCl3, 300 MHz) d (ppm) 2.09

47

(d, J = 2.4 Hz, 1H), 2.73–2.78 (m, 2H), 4.77 (dd, J = 12.6, 6.6 Hz, 1H), 5.30 (d, J = 6.6 Hz, 1H), 7.31 (d, J = 9.0 Hz, 2H), 7.35 (d, J = 6.0 Hz, 2H). 19F NMR (CDCl3, 282 MHz) d (ppm) 66.56 (s, 2F), 114.73 (d, JFF = 232.7 Hz, 1F), 120.28 (d, JFF = 232.7 Hz, 1F). 13C NMR (CDCl3, 100 MHz) d (ppm) 28.4, 55.3, 73.0, 78.4, 128.3, 129.2, 134.6, 137.8. HRMS (ESI) calcd for C12H9Cl2F4NOSNa [M + Na]+ 383.9610, found 383.9629. 4.2.2. (4S,Ss)-N-(2-Chlorotetrafluoroethanesulfinyl)-4-phenylbut-1yne-4-amine (7b) Colorless oil. FT-IR (film) 3311, 2362, 1497, 1263, 906, 803, 701 cm1. 1H NMR (CDCl3, 400 MHz) d (ppm) 2.09 (t, J = 2.6 Hz, 1H), 2.78–2.81 (m, 2H), 4.77 (dd, J = 12.6, 6.4 Hz, 1H), 5.23 (d, J = 6.4 Hz, 1H), 7.33–7.40 (m, 5H). 19F NMR (CDCl3, 282 MHz) d (ppm) 66.97 (s, 2F), 115.72 (d, JFF = 233.8 Hz, 1F), 120.70 (d, JFF = 233.8 Hz, 1F). 13C NMR (CDCl3, 100 MHz) d (ppm) 28.4, 56.5, 72.7, 78.9, 126.9, 129.0, 128.7, 139.2. HRMS (ESI) calcd for C12H10ClF4NOSNa [M + Na]+ 350.0000, found 349.9998; ½a26 D 44.4 (c 1.0, CHCl3). 4.2.3. (4S,Ss)-N-(2-Chlorotetrafluoroethanesulfinyl)-4-(mchlorophenyl)but-1-yne-4-amine (7c) Colorless oil. FT-IR (film) 3302, 2927, 1598, 1577, 1479, 1434, 1262, 905, 794, 696 cm1. 1H NMR (CDCl3, 300 MHz) d (ppm) 2.09– 2.14 (m, 1H), 2.76–2.82 (m, 2H), 4.77 (dd, J = 12.8, 6.3 Hz, 1H), 5.17 (d, J = 6.9 Hz, 1H), 7.27 (dd, J = 2.7, 2.7 Hz, 1H), 7.32–7.34 (m, 2H), 7.36 (s, 1H). 19F NMR (CDCl3, 282 MHz) d (ppm) 66.35 (s, 2F), 114.43 (d, JFF = 233.8 Hz, 1F), 120.19 (d, JFF = 233.8 Hz, 1F). 13C NMR (CDCl3, 100 MHz) d (ppm) 28.3, 55.2, 73.0, 78.2, 125.0, 126.1, 127.0, 128.8, 130.2, 134.8. HRMS (ESI) calcd for C12H9Cl2F4NOSNa [M + Na]+ 383.9610, found 383.9608. 4.2.4. (4S,Ss)-N-(2-Chlorotetrafluoroethanesulfinyl)-4-(ochlorophenyl)but-1-yne-4-amine (7d) Colorless oil. FT-IR (film) 3307, 2926, 2360, 1574, 1421, 1262, 1018, 903, 797, 751, 552 cm1. 1H NMR (CDCl3, 300 MHz) d (ppm) 2.11 (t, J = 2.4 Hz, 1H), 2.80–2.86 (m, 2H), 5.26 (dd, J = 13.2, 5.4 Hz, 1H), 5.39 (d, J = 7.8 Hz, 1H), 7.28–7.50 (m, 4H). 19F NMR (CDCl3, 282 MHz) d (ppm) 66.59 (s, 2F), 114.62 (d, JFF = 233.8 Hz, 1F), 120.95 (d, JFF = 233.8 Hz, 1F). 13C NMR (CDCl3, 100 MHz) d (ppm) 27.0, 52.2, 73.0, 78.2, 127.3, 128.4, 129.7, 130.1, 132.5, 136.8. HRMS (ESI) calcd for C12H9Cl2F4NOSNa [M + Na]+ 383.9610, found 383.9607. 4.2.5. (4S,Ss)-N-(2-Chlorotetrafluoroethanesulfinyl)-4-(pfluorophenyl)but-1-yne-4-amine (7e) Colorless oil. FT-IR (film) 3308, 2928, 1606, 1514, 1428, 1263, 1175, 1013, 908, 796, 652 cm1. 1H NMR (CDCl3, 300 MHz) d (ppm) 2.10 (d, J = 2.4 Hz, 1H), 2.75–2.79 (m, 2H), 4.76 (dd, J = 12.3, 6.3 Hz, 1H), 5.25 (d, J = 6.3 Hz, 1H), 7.04–7.14 (m, 2H), 7.34–7.38 (m, 2H). 19 F NMR (CDCl3, 282 MHz) d (ppm) 66.79 (s, 2F), 113.02 to 113.10 (m, 1F), 115.28 (d, JFF = 232.7 Hz, 1F), 120.43 (d, JFF = 232.7 Hz, 1F). 13C NMR (CDCl3, 100 MHz) d (ppm) 28.4, 55.6, 72.9, 78.6, 116.0 (d, J = 21.9 Hz), 128.7 (d, J = 8.0 Hz), 135.1, 162.8 (d, J = 246.5 Hz). HRMS (ESI) calcd for C12H9ClF5NOSNa [M + Na]+ 367.9906, found 367.9904. 4.2.6. (4S,Ss)-N-(2-Chlorotetrafluoroethanesulfinyl)-4-(ofluorophenyl)but-1-yne-4-amine (7f) Colorless oil. FT-IR (film) 3310, 2918, 2361, 1618, 1588, 1492, 1459, 1263, 1170, 1012, 909, 801, 759, 655 cm1. 1H NMR (CDCl3, 300 MHz) d (ppm) 2.08 (t, J = 2.6 Hz, 1H), 2.81–2.89 (m, 2H), 5.02–5.09 (m, 1H), 5.26 (d, J = 8.4 Hz, 1H), 7.06–7.23 (m, 2H), 7.29–7.43 (m, 2H). 19F NMR (CDCl3, 282 MHz) d (ppm) 66.56 (s, 2F), 114.85 (d, JFF = 229.6 Hz, 1F), 117.90 (s, 1F), 120.41 (d, JFF = 229.6 Hz, 1F). 13C NMR (CDCl3, 100 MHz) d (ppm) 27.7,

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51.1, 72.7, 78.5, 116.0 (d, J = 21.9 Hz), 124.6 (d, J = 3.7 Hz), 126.7 (d, J = 13.1 Hz), 128.6 (d, J = 3.6 Hz), 130.4 (d, J = 8.7 Hz), 160.2 (d, J = 245.0 Hz). HRMS (ESI) calcd for C12H9ClF5NOSNa [M + Na]+ 367.9906, found 367.9904. 4.2.7. (4S,Ss)-N-(2-Chlorotetrafluoroethanesulfinyl)-4-(pbromophenyl)but-1-yne-4-amine (7g) Colorless oil. FT-IR (film) 3296, 2927, 2357, 2121, 1899, 1593, 1489, 1419, 1262, 1165, 799, 669 cm1. 1H NMR (CDCl3, 300 MHz) d (ppm) 2.11 (t, J = 1.2 Hz, 1H), 2.76–2.80 (m, 2H), 4.77 (dd, J = 11.9, 5.9 Hz, 1H), 5.14 (d, J = 6.0 Hz, 1H), 7.26 (d, J = 6.9 Hz, 2H), 7.52 (d, J = 8.1 Hz, 2H). 19F NMR (CDCl3, 282 MHz) d (ppm) 66.57 (s, 2F), 114.91 (d, JFF = 233.8 Hz, 1F), 120.29 (d, JFF = 233.8 Hz, 1F). 13C NMR (CDCl3, 100 MHz) d (ppm) 29.8, 55.3, 73.2, 78.3, 127.7, 128.6, 132.2, 138.3. HRMS (ESI) calcd for C12H9BrClF4NOSNa [M + Na]+ 427.9105, found 427.9099. 4.2.8. (4S,Ss)-N-(2-Chlorotetrafluoroethanesulfinyl)-4-(pmethylphenyl)but-1-yne-4-amine (7h) Colorless oil. FT-IR (film) 3308, 2925, 2123, 1516, 1428, 1262, 1015, 905, 798, 667 cm1. 1H NMR (CDCl3, 300 MHz) d (ppm) 2.05 (t, J = 1.8 Hz, 1H), 2.33 (s, 3H), 2.73–2.75 (m, 2H), 4.68 (dd, J = 16.9, 6.0 Hz, 1H), 5.22 (d, J = 6.0 Hz, 1H), 7.17 (d, J = 7.8 Hz, 2H), 7.24 (d, J = 7.8 Hz, 2H). 19F NMR (CDCl3, 282 MHz) d (ppm) 66.40 (s, 2F), 115.24 (d, JFF = 233.8 Hz, 1F), 120.08 (d, JFF = 233.8 Hz, 1F). 13C NMR (CDCl3, 100 MHz) d (ppm) 21.2, 28.3, 56.5, 72.5, 79.0, 126.8, 129.7, 136.2, 138.6. HRMS (ESI) calcd for C13H12ClF4NOSNa [M + Na]+ 364.0157, found 364.0153. 4.2.9. (4S,Ss)-N-(2-Chlorotetrafluoroethanesulfinyl)-4-(pphenylphenyl)but-1-yne-4-amine (7i) Colorless oil. FT-IR (film) 3299, 2361, 1600, 1488, 1420, 1262, 1016, 905, 797, 736, 698 cm1; 1H NMR (CDCl3, 300 MHz) d (ppm) 2.14 (d, J = 2.4 Hz, 1H), 2.85 (t, J = 3.0 Hz, 2H), 4.83 (dd, J = 12.0, 5.7 Hz, 1H), 5.36 (d, J = 6.9 Hz, 1H), 7.36–7.48 (m, 5H), 7.61 (d, J = 7.8 Hz, 2H), 7.63 (d, J = 7.8 Hz, 2H). 19F NMR (CDCl3, 282 MHz) d (ppm) 66.05 (s, 2F), 114.61 (d, JFF = 233.8 Hz, 1F), 119.78 (d, JFF = 233.8 Hz, 1F). 13C NMR (CDCl3, 100 MHz) d (ppm) 28.3, 56.3, 72.7, 78.9, 127.3, 127.6, 127.7, 127.8, 128.9, 138.2, 140.4, 141.6. HRMS (ESI) calcd for C18H14ClF4NOSNa [M + Na]+ 426.0313, found 426.0308. 4.2.10. (4S,Ss)-N-(2-Chlorotetrafluoroethanesulfinyl)-4-(ptrifluoromethylphenyl)but-1-yne-4-amine (7j) Colorless oil. FT-IR (film) 3174, 2923, 1621, 1428, 1327, 1263, 1178, 1069, 908, 844, 801, 604 cm1. 1H NMR (CDCl3, 300 MHz) d (ppm) 2.11 (t, J = 2.6 Hz, 1H), 2.71–2.89 (m, 2H), 4.88 (dd, J = 12.5, 5.9 Hz, 1H), 5.45 (d, J = 7.5 Hz, 1H), 7.51 (d, J = 8.1 Hz, 2H), 7.65 (d, J = 8.1 Hz, 2H). 19F NMR (CDCl3, 282 MHz) d (ppm) 62.40 (s, 3F), 66.62 (s, 2F), 114.31 (d, JFF = 237.7 Hz, 1F), 120.53 (d, JFF = 237.7 Hz, 1F). 13C NMR (CDCl3, 100 MHz) d (ppm) 28.5, 55.1, 73.3, 78.1, 125.9 (q, J = 3.7 Hz), 127.3, 127.7, 130.9 (q, J = 32.3 Hz), 143.3. HRMS (ESI) calcd for C13H9ClF7NOSNa [M + Na]+ 417.9874, found 417.9860. 4.2.11. (4S,Ss)-N-(2-Chlorotetrafluoroethanesulfinyl)-4-(pmethoxyphenyl)but-1-yne-4-amine (7k) Colorless oil. FT-IR (film) 3293, 2927, 2277, 1612, 1517, 1251, 1176, 1015, 797, 650 cm1. 1H NMR (CDCl3, 300 MHz) d (ppm) 2.09 (t, J = 2.6 Hz, 1H), 2.75–2.78 (m, 2H), 3.80 (s, 3H), 4.70 (dd, J = 12.0, 6.0 Hz, 1H), 5.16 (d, J = 5.7 Hz, 1H), 6.90 (d, J = 8.7 Hz, 2H), 7.30 (d, J = 8.7 Hz, 2H). 19F NMR (CDCl3, 282 MHz) d (ppm) 66.70 (s, 2F), 115.83 (d, JFF = 233.5 Hz, 1F), 120.23 (d, JFF = 233.5 Hz, 1F). 13C NMR (CDCl3, 100 MHz) d (ppm) 28.3, 55.4, 56.4, 72.5, 79.1, 114.4, 128.2, 131.2, 159.9. HRMS (ESI) calcd for C13H12ClF4NO2SNa [M + Na]+ 380.0106, found 380.0120.

4.2.12. (4S,Ss)-N-(2-Chlorotetrafluoroethanesulfinyl)-4-(2furyl)but-1-yne-4-amine (7l) Colorless oil. FT-IR (film) 3293, 2923, 1611, 1423, 1257, 1177, 1017, 914, 799, 734, 651 cm1. 1H NMR (CDCl3, 300 MHz) d (ppm) 2.08 (d, J = 2.6 Hz, 1H), 2.82–2.84 (m, 2H), 4.79 (dd, J = 14.3, 6.8 Hz, 1H), 5.21 (d, J = 7.8 Hz, 1H), 6.34 (dd, J = 3.3, 1.7 Hz, 1H), 6.41 (d, J = 3.3 Hz, 1H), 7.40 (dd, J = 0.8, 0.8 Hz, 1H). 19F NMR (CDCl3, 282 MHz) d (ppm) 66.73 (s, 2F), 115.58 (d, JFF = 233.8 Hz, 1F), 120.15 (d, JFF = 233.8 Hz, 1F). 13C NMR (CDCl3, 100 MHz) d (ppm) 26.0, 51.4, 72.4, 78.6, 108.4, 110.6, 143.1, 151.6. HRMS (ESI) calcd for C10H8ClF4NO2SNa [M + Na]+ 339.9793, found 339.9808. 4.2.13. (4S,Ss)-N-(2-Chlorotetrafluoroethanesulfinyl)-4-(2thienyl)but-1-yne-4-amine (7m) Colorless oil. FT-IR (film) 3311, 2926, 1922, 1621, 1427, 1330, 1262, 1170, 907, 793, 667 cm1. 1H NMR (CDCl3, 400 MHz) d (ppm) 2.14 (t, J = 2.6 Hz, 1H), 2.82–2.94 (m, 2H), 5.02 (dd, J = 12.8, 6.0 Hz, 1H), 5.18 (d, J = 4.8 Hz, 1H), 7.00 (dd, J = 4.8, 3.6 Hz, 1H), 7.13 (d, J = 3.6 Hz, 1H), 7.31 (dd, J = 5.2, 1.2 Hz, 1H). 19F NMR (CDCl3, 282 MHz) d (ppm) 66.43 (s, 2F), 114.91 (d, JFF = 232.7 Hz, 1F), 119.88 (d, JFF = 232.7 Hz, 1F). 13C NMR (CDCl3, 100 MHz) d (ppm) 29.0, 53.0, 73.1, 78.6, 126.1, 126.3, 127.2, 142.4. HRMS (ESI) calcd for C10H8ClF4NOS2Na [M + Na]+ 355.9564, found 355.9557. 4.2.14. (4S,Ss)-N-(2-Chlorotetrafluoroethanesulfinyl)-4(cyclohexyl)but-1-yne-4-amine (7o) Colorless oil. FT-IR (film) 3312, 2926, 2854, 1723, 1452, 1263, 1173, 1014, 907, 795, 736, 648 cm1. 1H NMR (CDCl3, 300 MHz) d (ppm) 1.14–1.28 (m, 3H), 1.56–1.69 (m, 3H), 1.75–1.79 (m, 3H), 1.90 (s, 1H), 2.03–2.07 (m, 1H), 2.45–2.50 (m, 2H), 3.13 (t, J = 2.3 Hz, 1H), 3.24–3.33 (m, 1H), 4.59 (dd, J = 10.2, 9.6 Hz, 1H). 19F NMR (CDCl3, 282 MHz) d (ppm) 66.68 (s, 2F), 115.21 (d, JFF = 234.9 Hz, 1F), 122.10 (d, JFF = 234.9 Hz, 1F). 13C NMR (CDCl3, 100 MHz) d (ppm) 24.4, 26.1, 28.8, 29.7, 41.5, 60.6, 71.7, 76.3, 78.2. HRMS (ESI) calcd for C12H16ClF4NOSNa [M + Na]+ 356.0470, found 356.0467. 4.2.15. (4S,Ss)-N-(2-Chlorotetrafluoroethanesulfinyl)-4(isopropyl)but-1-yne-4-amine (7p) Colorless oil. FT-IR (film) 3313, 2967, 1467, 1263, 1177, 1012, 908, 795, 647 cm1. 1H NMR (CDCl3, 300 MHz) d (ppm) 1.01 (d, J = 1.8 Hz, 3H), 1.03 (d, J = 1.8 Hz, 3H), 1.25 (s, 1H), 2.05 (t, J = 2.9 Hz, 1H), 2.49 (dd, J = 5.6, 2.6 Hz, 2H), 3.29–3.37 (m, 1H), 4.58 (d, J = 9.0 Hz, 1H). 19F NMR (CDCl3, 282 MHz) d (ppm) 66.68 (s, 2F), 115.18 (d, JFF = 234.6 Hz, 1F), 122.03 (d, JFF = 234.6 Hz, 1F). 13C NMR (CDCl3, 100 MHz) d (ppm) 18.3, 19.4, 24.5, 31.9, 60.8, 71.7, 79.4. HRMS (ESI) calcd for C9H12ClF4NOSNa [M + Na]+ 316.0157, found 316.0163. 4.2.16. (4S,Ss)-N-(2-Chlorotetrafluoroethanesulfinyl)-4-(2phenylvinyl)but-1-yne-4-amine (7q) White powder. mp 31–32 8C. FT-IR (KBr) 3274, 2915, 1494, 1259, 1172, 1015, 970, 907, 747, 692 cm1. 1H NMR (CDCl3, 300 MHz) d (ppm) 2.13 (dd, J = 3.5, 1.7 Hz, 1H), 2.57–2.73 (m, 2H), 4.35 (ddd, J = 12.9, 6.3, 6.3 Hz, 1H), 4.97 (d, J = 7.8 Hz, 1H), 6.25 (dd, J = 15.9, 6.6 Hz, 1H), 6.68 (d, J = 15.9 Hz, 1H), 7.24–7.30 (m, 3H), 7.33–7.41 (m, 2H). 19F NMR (CDCl3, 282 MHz) d (ppm) 69.20 (s, 2F), 118.15 (d, JFF = 233.8 Hz, 1F), 122.71 (d, JFF = 233.8 Hz, 1F). 13 C NMR (CDCl3, 100 MHz) d (ppm) 27.2, 55.2, 72.6, 78.7, 126.9, 127.1, 128.5, 128.8, 133.6, 135.9. HRMS (ESI) calcd for C14H12ClF4NOSNa [M + Na]+ 376.0156, found 376.0167. 4.2.17. (4S,Ss)-N-(2-Chlorotetrafluoroethanesulfinyl)-4-(2phenylvinyl)but-1-yne-4-amine (7q0 ) White powder. mp 40–42 8C. FT-IR (film) 3305, 2924, 1738, 1365, 1230, 909, 798, 693 cm1. 1H NMR (CDCl3, 300 MHz) d (ppm) 1.03 (d, J = 1.8 Hz, 3H), 1.25 (s, 1H), 2.05 (t, J = 2.9 Hz, 1H), 2.49

L.-J. Liu, J.-T. Liu / Journal of Fluorine Chemistry 168 (2014) 44–49

(dd, J = 5.6, 2.6 Hz, 2H), 2.18 (dd, J = 2.6, 2.6 Hz, 1H), 2.57–2.75 (m, 2H), 4.35 (ddd, J = 12.3, 6.1, 6.1 Hz, 1H), 4.93 (d, J = 5.1 Hz, 1H), 6.10 (dd, J = 15.9, 7.7 Hz, 1H), 6.71 (d, J = 16.2 Hz, 1H), 7.29–7.42 (m, 5H). 19F NMR (CDCl3, 282 MHz) d (ppm) 66.42 to 66.53 (m, 2F), 117.30 (d, JFF = 233.5 Hz, 1F), 118.73 (d, JFF = 233.5 Hz, 1F). 13 C NMR (CDCl3, 100 MHz) d (ppm) 27.1, 55.9, 72.9, 78.7, 126.3, 126.9, 128.7, 128.9, 134.8, 135.7. HRMS (ESI) calcd for C 14 H 12 ClF 4NOSNa [M + Na] + 376.0156, found 376.0149. 4.2.18. (3S,4S,Ss)-N-(2-Chlorotetrafluoroethanesulfinyl)-1-phenyl4-(4-chlorophenyl)but-1-yne-4-amine (7s) White powder. mp 70–71 8C. FT-IR (KBr) 3223, 2896, 1597, 1492, 1264, 916, 794, 755, 690 cm1. 1H NMR (300 MHz, CDCl3) d (ppm) 2.87–2.96 (m, 2H), 4.80 (dd, J = 12.9, 6.0 Hz, 1H), 5.26 (d, J = 14.1 Hz, 1H), 7.25–7.36 (m, 9H). 19F NMR (282 MHz, CDCl3) d (ppm) 66.77 (s, 2F), 114.99 (d, JFF = 233.8 Hz, 1F), 120.61 (d, JFF = 233.8 Hz, 1F). 13C NMR (100 MHz, CDCl3) d (ppm) 29.5, 55.6, 83.6, 85.0, 122.7, 128.3, 128.4, 128.5, 129.2, 131.7, 134.6, 138.1. HRMS (EI) calcd for C18H13Cl2F4NOSNa [M + Na]+ 459.9923, found 459.9942. 4.2.19. (S,Ss)-N-(2-Chlorotetrafluoroethanesulfinyl)-1-(4chlorophenyl)-2-methylbuta-2,3-dien-1-amine (7t) Colorless oil. FT-IR (film) 3224, 2921, 1959, 1597, 1261, 1165, 1015, 909 cm1. 1H NMR (300 MHz, CDCl3) d (ppm) 1.57–1.62 (m, 3H), 4.95–5.02 (m, 4H), 7.25–7.40 (m, 4H). 19F NMR (282 MHz, CDCl3) d (ppm) 66.70 (s, 2F), 115.96 (d, JFF = 236.9 Hz, 1F), 119.60 (d, JFF = 236.9 Hz, 1F). 13C NMR (100 MHz, CDCl3) d (ppm) 15.6, 59.1, 79.1, 99.8, 128.8, 129.2, 134.5, 137.7, 206.0. HRMS (EI) calcd for C13H11Cl2F4NOSNa [M + Na]+ 397.9767, found 397.9772. 4.2.20. (4S,Ss)-N-(2-Chlorotetrafluoroethanesulfinyl)-3,3-dimethyl4-(4-chlorophenyl)but-1-yne-4-amine (7u) Colorless oil. FT-IR (film) 3305, 2981, 1598, 1494, 1260, 1172, 907, 792, 668 cm1. 1H NMR (300 MHz, CDCl3) d (ppm) 1.03 (s, 3H), 1.42 (s, 3H), 2.37 (s, 1H), 4.19 (d, J = 9.0 Hz, 1H), 5.35 (d, J = 8.7 Hz, 1H), 7.26–7.36 (m, 4H). 19F NMR (282 MHz, CDCl3) d (ppm) 66.85 (s, 2F), 113.13 (d, JFF = 247.5 Hz, 1F), 121.71 (d, JFF = 247.5, 4.3 Hz, 1F). 13C NMR (100 MHz, CDCl3) d (ppm) 26.8, 28.7, 37.4, 64.1, 73.2, 86.6, 128.6, 129.6, 134.6, 136.9. HRMS (ESI) calcd for C14H13Cl2F4NOSNa [M + Na]+ 411.9923, found 411.9937. 4.3. The reaction of 6a with 5a in the absence of Ti(Oi-Pr)4 To a mixture of imine 6a (1.0 mmol), zinc power (2.0 mmol) and THF (2.0 mL) was added CuCl (0.1 mmol) and 5a (2.0 mmol). The resulting mixture was stirred at 50 8C and monitored by 19F NMR. No 7a was detected after 8 h and most of 6a remained unchanged. 4.4. Procedure for the synthesis of 9b A mixture of 7b (0.15 mmol), 4 M HCl (0.5 mL, in dioxane) was stirred at 45 8C for 1 h (monitored by TLC). After cooled to room temperature, solvent was removed under reduced pressure, 8b was obtained as a white solid and used in next step without further purification. To a solution of 8b in CH2Cl2 (5.0 mL) were added pyridine (0.75 mmol) and p-toluenesulfonyl chloride (0.75 mmol). The mixture was stirred at room temperature. After completion of the reaction, the solution was washed with aqueous solution of

49

CuSO4 (5.0 mL  3), water (5.0 mL) and brine in sequence. The organic phrase was dried over anhydrous Na2SO4, concentrated and purified by column chromatography (EA/PE: 1/5) to give 9b. 4.4.1. (4S)-N-(p-methylphenylsulfonyl)-4-phenylbut-1-yne-4-amine (9b) Colorless oil. 1H NMR (CDCl3, 300 MHz) d (ppm) 1.98 (t, J = 2.4 Hz, 1H), 2.38 (s, 3H), 2.64 (dd, J = 5.9, 2.6 Hz, 2H), 4.50 (dd, J = 12.6, 6.3 Hz, 1H), 5.24 (d, J = 7.2 Hz, 1H), 7.22–7.17 (m, 7H), 7.62 (d, J = 8.1 Hz, 2H). EI-MS (m/z, %) 260 (64.46), 155 (54.66), 91 (100.00). ½a26 D 60.4 (c 1.0, CHCl3). Acknowledgement Financial support from the National Natural Science Foundation of China (No. 21172243) is gratefully acknowledged.

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