![logo2](/ServeContent?url=http%3A%2F%2Fwww.heterocycles.jp%2Fclockss%2Fimg%2Fcycle.gif)
![logo2](/ServeContent?url=http%3A%2F%2Fwww.heterocycles.jp%2Fclockss%2Fimg%2Flogo_box.gif)
HETEROCYCLES
An International Journal for Reviews and Communications in Heterocyclic ChemistryWeb Edition ISSN: 1881-0942
Published online by The Japan Institute of Heterocyclic Chemistry
e-Journal
Full Text HTML
Received, 6th June, 2013, Accepted, 4th July, 2013, Published online, 16th July, 2013.
DOI: 10.3987/COM-13-S(S)27
■ Diastereoselective Synthesis of 3-Fluoro-2-substituted Piperidines and Pyrrolidines
Paul N. Gichuhi, Masami Kuriyama, and Osamu Onomura*
Department of Natural Product Chemistry, Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan
Abstract
A facile procedure for synthesis of trans-3-fluoro-2-substituted piperidines by utilizing electrophilic fluorination of cyclic enamines and Lewis acid mediated nucleophilic substitution has been developed. Also, optically active trans-2-allyl-3-fluorinated pyrrolidines have been prepared by utilizing nucleophilic fluorination of hydroxyl group of trans-hydroxy-L-proline and Lewis acid mediated diastereoselective allylation as key steps.INTRODUCTION
N-Heterocycles such as substituted piperidine or pyrrolidines are vast substructures in a great number of biologically active natural products and small molecule pharmaceuticals.1 Since fluorinated compounds exhibit distinctive biological and physical properties, fluorinated N-heterocycles are of great interest in areas such as; material science, agrochemicals, and pharmaceuticals (Figure 1).2 To date, both electrophilic and nucleophilic fluorination methods have been developed to furnish fluorinated N-heterocycles.3,4
In addition, the nucleophilic additions to N-acyliminium ions are powerful methods for synthesis of biologically active N-heterocycles.5 Also, a large number of methods containing diastereoselective reactions to furnish substituted piperidines and pyrrolidines have been developed.6 An example of such addition reaction to N-acyliminium ion in which a fluorine atom present on the ring influences the stereochemistry of the adducts is uniquely important. Hence the synthesis of stereo defined fluorinated cyclic amine derivatives with nucleophilic addition to N-acyliminium ion has not yet been reported. Herein, we describe a facile synthesis using an electrophilic fluorinating reagent SelectfluorTM 17 utilizing N-acyliminium ion precursors to furnish 3-fluorinated derivatives, where the fluorine atom on the ring influences the diastereoselectivities of adducts. The significance of this method is threefold: (Step 1) Preparation of N-protected cyclic enamines 4 from corresponding amines 2 using the electrochemical oxidation method8 and demethoxylation of 3.9 (Step 2) Electrophilic fluorination of 4 using 1, which is safe, non-toxic, and easy to handle (Eq. 1).10,11 (Step 3) Lewis acid mediated nucleophilic substitution of 5 to give trans-substituted derivatives 6 or 7 (Eq. 2).
In addition, a nucleophilic fluorination with XtalFluor-ETM 812 of N-Cbz-trans-4-hydroxy-L-prolinate 9 afforded cis-fluoro-L-prolinate 10 which was electrochemically transformed into methoxylated derivative 11. Successive diastereoselective allylation of 11 afforded optically active allylated derivative 12 which was easily transformed into 2R-allyl-3S-fluoropyrrolidine 13 (Eq. 3).13
RESULTS AND DISCUSSION
Preparation of N-protected enamines 4a-f from the respective N-protected piperidines and pyrrolidines was achieved according to Shono method which consists of electrochemical methoxylation and successive removal of methanol with up to 97% yield.8,9 Next, electrophilic fluorination of substrates 4a-f using SelectfluorTM 1 afforded 3-fluoro-2-methoxy-N-protected piperidine and pyrrolidine derivatives.7,10 Namely, addition of 1 to a solution of 4 in acetonitrile/methanol gave 5a-f in good yields (Table 1).
We envisaged that upon treatment of 5 with some Lewis acids, the N-acyliminium ions was generated and readily trapped by the carbon nucleophiles resulting to the desired products with fluorine atom influencing the diastereoselectivities.13,14 To our delight, when compounds 5 were treated with some Lewis acids in CH2Cl2, the allylation using allyltrimethylsilane proceeded satisfactorily to give allylated products 6 in good yields (Table 2). TiCl4 or BF3·OEt2 mediated allylation of 3-fluoro-2-methoxy-N-methoxycarbonylpiperidine 5a smoothly proceeded to afford the allylated product 6a in high yields with moderate diastereoselectivities (entries 1 and 2). For allylation of N-phenyloxycarbonylated piperidine 5b, the higher diastereoselectivity was achieved by using TiCl4 affording 58% de and 81% yield compared with BF3·OEt2 (entries 3 and 4). Although TiCl4 did not result to the allylated product for N-benzyloxycarbonylated piperidine 5d, using BF3·OEt2 gave 58% de and 87% yield (entries 6 and 7).15 On the other hand, SnCl4 did not lead to any improvement on the de value of 6d (entry 8). In addition, BF3·OEt2 mediated allylation of pyrrolidine derivatives 5c,e proceeded to afford substituted products 6c,e in high yields with low diastereoselectivities (entries 5 and 9).
Next we focused on cyanation of 5. When compounds 5a,b,d were treated with trimethylsilyl cyanide in the presence of TiCl4, the desired product was formed in high yields and moderate diastereoselectivities as shown in Table 3 (entries 1-3). Also, 2-cyano-3-fluoro-N-benzyloxycarbonylpiperidine 7d was formed with a higher de of 58% and yield of 84% when mediated by BF3·OEt2 as the Lewis acid of choice (entry 4). SnCl4 did not lead to an improvement of the de and the yield of 7d (entry 5).
Relative stereoconfigurations for 6 and 7 were speculated by the NOESY studies for 6d and the HMBC studies16 for 7d. Diastereomers of 6d or 7d were separable by silica gel PTLC to afford major isomer and minor isomer, respectively. The NOESY spectroscopy for major isomer of 6d showed correlations, while the NOESY spectroscopy for minor isomer of 6d did not show the correlation. Accordingly, it was determined that major isomer was trans-6d and minor isomer was cis-6d. Similarly separated major isomer for 7d was determined as trans configuration (Figure 2).
We next focused on the synthesis of optically active 2-allyl-3-fluoropyrrolidine starting from N-Cbz-trans-4-hydroxy-L-prolinate 9.17 Deoxofluorination of 9 was achieved by utilizing XtalFluor-ETM 8 as the reagent of choice.12 The fluorination of the hydroxyl group at the 4-position proceeded in an inversion manner to give the desired compound 10 in 82% yield.12,18 Electrochemical oxidation of 10 afforded 4-fluoro-5-methoxy-L-proline derivative 11 in 74% yield (Eq. 4).
The allylation of 11 using 2.0 equiv of Lewis acids19 was successfully achieved affording compound 12 (Eq. 5).13 In the case of N-benzyloxycarbonylprolinate 11, the allylation mediated by TiCl4 resulted to good yield and de. Using BF3·OEt2 afforded 12 in higher yield and de (entry 2), while the use of SnCl4 afforded low yield and de of 12.
Hydrolysis, successive decarboxylative methoxylation, and reductive demethoxylation13 of 12 prepared by using BF3·OEt2 proceeded smoothly without purification of intermediate 14 to give 2-allyl-3S-fluoropyrrolidine 13 (Eq. 6).
Comparing HPLC pattern of 13 with that of 6e (trans/cis=63:37) showed that the relative stereoconfiguration of 13 was majorly trans (82% de) and its absolute stereoconfiguration was 2R,3S.
CONCLUSION
In conclusion, a facile procedure for synthesis of trans-3-fluoro-2-substituted piperidines and optically active trans-2-allyl-3-fluorinated pyrrolidine which can be used as precursors for new drugs in pharmaceuticals has been developed. This was achieved by utilizing facile electrochemical oxidation and electrophilic or nucleophilic fluorination. Additionally, mild conditions and practical convenience will make this method a valuable synthetic tool in organic chemistry.
EXPERIMENTAL
General: All commercial materials, reagents and solvents, were used without further purification unless otherwise stated. Electrochemical reactions were carried out by the use of DC power supply (GP 050-2) of Takasago Seikakusho in an undivided glass cell by using platinum plate electrodes (10 x 20 mm), graphite electrodes (50 x 12 x 2 mm). 1H NMR spectra were measured at 500 and 400 MHz with TMS as an internal standard at 50 oC, 19F NMR spectra were measured at 376 MHz with CFCl3 used as the internal standard at 50 oC. 13C NMR spectra were measured at 100MHz on JEOL JNM-AL 400MHZ. IR spectra were obtained on Shimadzu FTIR-8100A. High resolution mass spectra were recorded on a JEOL JMS-700N instrument using electron ionization (EI) mass spectrometry. Melting points were measured with micro melting point apparatus (Yanaco). Flash column chromatography was performed using silica gel 60 (230-400 mesh, Nacalai tesque) with the indicated solvents. Thin-layer chromatography was performed using 0.25 mm silica gel plates (Merck). Specific optical rotations were recorded on JASCO DIP-1000 digital polarimeter.
General procedure for the preparation of N-protected enamines 4a-f
The substrates 4a-i were prepared from the respective N-protected piperidine and pyrrolidines according to previously reported methods.8,9 Compounds 4a,8 4b,20 4c,21 4d,22 4e,9 and 4f23 are known compounds and their spectroscopic data is available in literature.
General procedure for the fluorination of N-protected enamines 4a-i using Selectfluor
To the substrates 4a-f (1.0 mmol) dissolved in 3 mL of MeCN/MeOH (1:1) under a nitrogen atmosphere, Selectfluor (1.1 mmol) was added at 0 oC stirring the mixture for 1 h. The temperature of the mixture was then gradually allowed to rise to room temperature and the reaction was monitored using TLC for over 2 h. Water (5 mL) was added and the mixture extracted using CH2Cl2 (5 x 10 mL). The combined organic layer was dried by anhydrous Na2SO4. The crude product was purified by column chromatography on silica gel (n-hexane/EtOAc 4:1) to give the desired product 5a-f.
3-Fluoro-2-methoxy-N-methoxycarbonylpiperidine (5a)
Colorless oil; 1H NMR (CDCl3) δ 1.42-1.65 (m, 1H), 1.73-2.03 (m, 3H), 2.85-2.99 (m, 1H), 3.30 and 3.36 (2s, 3H), 3.74 and 3.75 (2s, 3H), 3.81-4.03 (m, 1H), 4.35-4.52 and 4.61 (m and d, J=46.4 Hz, 1H), 5.20-5.55 (m, 1H); 13C NMR (CDCl3) δ 18.7 and 23.2 (2s), 24.1 and 24.2 (2s), 37.3 and 37.9 (2s), 52.4 and 52.5 (2s), 54.6 and 55.1 (2s), 82.2 and 82.5 (2s), 85.8 and 88.6 (2d, J=170.6 and 183.9 Hz), 156.7 and 155.9 (2s); 19F NMR (CDCl3) δ −191.2 (br s, 0.67F), −183.5 (d, J=47.3 Hz, 0.33F); IR (neat) 2953, 1701, 1440, 1412, 1369, 1261, 1163, 1086, 962, 770 cm−1. HR-MS [EI (+)]: m/z calcd for C8H14FNO3 [M+] 191.0958, found 191.0941.
3-Fluoro-2-methoxy-N-phenyloxycarbonylpiperidine (5b)
Mp 76-78 oC; 1H NMR (CDCl3) δ 1.52-1.68 (m, 1H), 1.75-2.07 (m, 3H), 3.05 (br s, 1H), 3.31-3.53 (m, 3H), 3.96-4.10 (m, 1H), 4.53 and 4.67 (br d and d, J=47.6 and 47.6 Hz, 1H), 5.51-5.62 (m, 1H), 7.09-7.36 (m, 5H); 13C NMR (CDCl3) δ 23.82-24.38 (m), 25.50 (br s), 38.19 (br s), 52.75-56.04 (m), 82.98 (br s), 84.88-86.79 (m), 121.06-121.76 (m, 2C), 124.67-125.60 (m), 128.75-129.40 (m, 2C), 150.89-151.35 (m), 153.61 (s); 19F NMR (CDCl3) δ −191.57 (t, J=45.1 Hz, 0.40F), −183.8 (t, J=47.1 Hz, 0.60F); IR (neat) 2945, 1717, 1495, 1410, 1381, 1369, 1260, 1198, 1161, 1069, 1024, 968, 748 cm−1. HR-MS [EI (+)]: m/z calcd for C13H16FNO3 [M+] 253.1114, found 253.1127.
3-Fluoro-2-methoxy-N-phenyloxycarbonylpyrrolidine (5c)
Colorless oil; 1H NMR (CDCl3) δ 2.20-2.31 (m, 2H), 3.48 and 3.58 (2s, 3H), 3.73-3.81 (m, 2H), 4.89-5.04 (m, 1H), 5.24-5.33 (m, 1H), 7.13-7.25 (m, 3H), 7.34-7.38 (m, 2H); 13C NMR (CDCl3) δ 28.17-29.96 (m), 41.37-46.30 (m), 56.04-57.97 (m), 86.39 (s), 91.49-95.59 (m), 121.92 (br s), 125.87 (s, 2C), 129.66 (s, 2C), 151.01 (2s), 153.02-154.84 (m); 19F NMR (CDCl3) δ −200.3 −201.5 (m, 0.37F), −186.9- −188.2 (m, 0.63F); IR (neat) 2936, 1721, 1593, 1495, 1456, 1387, 1371, 1204, 1163, 1099, 1042, 957, 731 cm−1. HR-MS [EI (+)]: m/z calcd for C12H14FNO3 [M+] 239.0958, found 239.0958.
N-Benzyloxycarbonyl-3-fluoro-2-methoxypiperidine (5d)
Colorless oil; 1H NMR (CDCl3) δ 1.40-1.54 (m, 1H), 1.69-2.05 (m, 3H), 2.89-2.95 (m, 1H), 3.25-3.62 (m, 3H), 3.68-4.00 (m, 1H), 4.33-4.50 and 4.59 (m and d, J=48.1 Hz, 1H), 5.06-5.27 (m, 2H), 5.46 (br s, 1H), 7.23-7.41 (m, 5H); 13C NMR (CDCl3) δ 18.9 and 23.3 (2s), 24.2 and 24.4 (2s), 37.5 and 38.1 (2s), 54.8 and 55.1 (2s), 67.2 and 67.4 (2s), 82.3 and 82.6 (2s), 85.9 and 88.7 (2s), 127.9 (s), 128.1 (s), 128.0 (s), 128.3 (s), 128.5 and 128.6 (2s), 136.2 and 136.5 (2s), 155.2 and 155.9 (2s); 19F NMR (CDCl3) δ −191.37(s, 0.50F), −183.67 (s, 0.50F); IR (neat) 2947, 1697, 1447, 1418, 1258, 1070, 962 cm−1. HR-MS [EI (+)]: m/z calcd for C14H18FNO3 [M+] 267.1271, found 267.1257.
N-Benzyloxycarbonyl-3-fluoro-2-methoxypyrrolidine (5e)
Colorless oil; 1H NMR (CDCl3) δ 2.03-2.15 (m, 2H), 3.18-3.47 (m, 4H), 3.57 (br s, 1H), 4.68-4.88 and 4.81 (m and d, J=52.4 Hz, 1H), 4.95-5.25 (m, 3H), 7.19-7.28 (m, 5H); 13C NMR (CDCl3) δ 29.82 (s), 41.55 (s), 43.71 and 45.62 (2s), 55.60 and 56.16 (2s), 86.55 (s), 91.65 (s), 127.72-128.58 (m, 5C), 136.19-136.35 (m), 155.17-155.79 (m); 19F NMR (CDCl3) δ −201.25 and −200.32 (2d, J=41.0, 51.9 Hz, 0.19F), −188.03 and −187.10 (2s, 0.81F); IR (neat) 2947, 1705, 1449, 1404, 1341, 1279, 1213, 1177, 1096, 1076, 959, 772 cm−1. HR-MS [EI (+)]: m/z calcd for C13H16FNO3 [M+] 253.1114, found: 253.1120.
N-Benzoyl-3-fluoro-2-methoxypiperidine (5f)
Colorless oil; 1H NMR (CDCl3) δ 1.45-2.23 (m, 4H), 2.94-3.52 (m, 4H), 4.15-6.10 (m, 3H), 7.39-7.48 (m, 5H); 13C NMR (CDCl3) δ 19.31 (br s), 24.62-25.03 (m), 36.22 (m), 54.85 and 55.6 (2s), 85.74-88.01 (m), 89.87 (br s), 127.23-127.80 (m, 2C), 128.68-128.89 (m, 2C), 130.03 and 130.42 (2s), 135.55 and 135.76 (2s), 171.65 and 172.38 (2s); 19F NMR (CDCl3) δ −191.24 (br s, 0.29F), −183.23 and −184.09 (2br s, 0.71F); IR (neat) 2945, 1641, 1412, 1352, 1301, 1273, 1069, 1045, 968, 702 cm−1. HR-MS [EI (+)]: m/z calcd for C13H16FNO2 [M+] 237.1165, found 237.1151.
General procedure for the preparation of 2-allyl-3-fluoro-N-protected cyclic amine derivatives 6a-e
The substrate compound 5 (1.0 mmol) and allyltrimethylsilane (3.0 mmol) were dissolved in dry CH2Cl2 (3 mL) at −78 oC, under nitrogen atmosphere. 1M TiCl4 in CH2Cl2 (1.1 mmol) was added dropwise via syringe. The reaction was allowed to warm to room temperature over 3 h, progress monitored by TLC. After completion, the reaction mixture was quenched with (5 mL) of saturated aqueous NaHCO3 solution. The aqueous layer was extracted with CH2Cl2 (3 x 5 mL) and the combined organic layer washed with saturated aqueous NaCl (10 mL) and dried over anhydrous Na2SO4. The organic layer was evaporated in vacuo, which was further purified by column chromatography on silica gel (n-hexane/EtOAc 8:1) as eluent giving a mixture of diastereoisomers compound 6.
2-Allyl-3-fluoro-N-methoxycarbonylpiperidine (6a) (44% de)
Colorless oil; 1H NMR (CDCl3) δ 1.34-1.52 (m, 1H), 1.58-1.78 (m, 2H), 1.80-1.97 (m, 1H), 2.13-2.39 (m, 2H), 2.68 (td, J=13.4, 3.1 Hz, 0.72H), 2.78-2.83 (m, 0.28H), 3.48-3.72 (m, 3H), 3.87 (d, J=12.2 Hz, 0.72H), 4.01 (d, J=9.8 Hz, 0.28H), 4.45-4.51 (m, 1H), 4.57-4.63 (m, 1H), 4.94-5.05 (m, 2H), 5.61-5.72 (m, 1H); 13C NMR (CDCl3) δ 19.65 (s), 24.96-25.24 (m), 25.90 (s), 33.63 and 33.72 (2s), 38.09 and 39.15 (2s), 53.01-54.12 (m), 87.98 and 89.74 (2d, J=184.0 and 170.5 Hz), 117.72 and 118.24 (2s), 134.29 and 134.72 (2s), 156.95 and 157.27 (2s); 19F NMR (CDCl3) δ −182.45 (br s, 0.28F), −181.51 (d, J=48.8 Hz, 0.72F); IR (neat) 2953, 1694, 1449, 1408, 1366, 1310, 1190, 1152, 1034, 959, 916, 766 cm−1. HR-MS [EI (+)]: m/z calcd for C10H16FNO2 [M+] 201.1165, found 201.1163.
2-Allyl-3-fluoro-N-phenyloxycarbonylpiperidine (6b) (58% de)
Mp 80-81 oC; 1H NMR (CDCl3) δ 1.57-1.72 (m, 2H), 1.73-1.91 (m, 1H), 1.87-2.15 (m, 1H), 2.34-2.58 (m, 2H), 4.09 (d, J=13.7 Hz, 0.79H), 4.22 (d, J=12.2 Hz, 0.21H), 4.56-4.87 (m, 2H), 4.99-5.25 (m, 2H), 5.15-5.66 (m, 1H), 5.70-5.95 (m, 1H), 7.01-7.13 (m, 2H), 7.13-7.21 (m, 1H), 7.27-7.39 (m, 2H); 13C NMR (CDCl3) δ 19.24 (s), 24.79 and 24.57 (2s), 33.24 and 33.33 (2s), 38.08 (br s), 53.84 (br s), 86.72 and 88.71 (2s), 115.73 (s), 118.0 (br s), 119.08 (s), 121.73 (s), 125.15 (s), 129.19 (s), 133.56 (s), 151.61 (s), 154.23 (s); 19F NMR (CDCl3) δ −178.91 and −179.55 (2b s, 1F); IR (neat) 2949, 1709, 1643, 1593, 1495, 1412, 1356, 1310, 1240, 1196, 1161, 1140, 1040, 1024, 991, 957, 743 cm−1. HR-MS [EI (+)]: m/z calcd for C15H18FNO2 [M+] 263.1322, found 263.1324.
2-Allyl-3-fluoro-N-phenyloxycarbonylpyrrolidine (6c) (14% de)
Colorless oil; 1H NMR (CDCl3) δ 1.79-2.67 (m, 4H), 2.81 and 3.42-4.28 (br s and m, 3H), 4.83-5.26 (m, 3H), 5.68-5.87 (m, 1H), 7.06-7.17 (m, 3H), 7.27-7.35 (m, 2H); 13C NMR (CDCl3) δ 28.54-31.62 (m), 35.72 and 36.78 (2br s), 44.65 (s), 62.11 and 63.99 (2br s), 91.86-94.26 (m), 117.88 (s), 118.15 (br s), 121.58 (s), 125.19 (s), 129.11 and 129.19 (2s), 133.48 (br s), 134.14 and 134.16 (2s), 151.33 and 151.35 (2s), 153.09 and 153.17 (2s); 19F NMR (CDCl3) δ −193.17 and −193.84 (2br s, 0.57F), −176.21- −175.20 (m, 0.43F); IR (neat) 2949, 1717, 1641, 1593, 1494, 1389, 1192, 1070, 1022, 918, 754, 739 cm−1. HR-MS [EI (+)]: m/z calcd for C14H16FNO2 [M+] 249.1165, found 249.1162.
2-Allyl-N-benzyloxycarbonyl-3-fluoropiperidine (6d) (58% de)
Colorless oil; 1H NMR (CDCl3) δ 1.42-1.64 (m, 2H), 1.68-1.83 (m, 1H), 1.88-2.05 (m, 1H), 2.35-2.47 (m, 2H), 2.78 (t, J=13.4 Hz, 0.79H), 2.88 (t, J=13.2 Hz, 0.21H), 4.00 (br d, J=13.9 Hz, 0.79H), 4.14 (br d, J=13.2 Hz, 0.21H), 4.50-4.72 (m, 2H), 4.95-5.20 (m, 4H), 5.62-5.78 (m, 1H), 7.33 (s, 5H); 13C NMR (CDCl3) δ 23.71 (s), 25.59 and 25.78 (2s), 28.88 (s), 37.96 and 39.01 (2s), 53.67 and 53.92 (2s), 67.46 and 67.64 (2s), 88.25 and 90.06 (2s), 117.63 and 118.11 (2s), 128.1-28.92 (m, 5C), 134.05 and 134.59 (2s), 137.14 and 137.40 (2s), 156.07 (s); 19F NMR (CDCl3) δ −181.48 (d, J=48.9 Hz, 1F); IR (neat) 2949, 1692, 1423, 1350, 1248, 1148, 1069, 1028, 1001, 959, 733 cm−1. HR-MS [EI (+)]: m/z calcd for C16H20FNO2 [M+] 277.1478, found 277.1458.
Further purification of a mixture of cis- and trans-6d by PTLC afforded cis-6d and trans-6d.
cis-2-Allyl-N-benzyloxycarbonyl-3-fluoropiperidine (cis-6d) (less polar)
Colorless oil; 1H NMR (CDCl3) δ 1.44-1.62 (m, 1H), 1.69-1.85 (m, 2H), 1.89-2.05 (m, 1H), 2.35-2.45 (m, 2H), 2.88 (t, J=13.4 Hz, 1H), 4.14 (d, J=13.7 Hz, 1H), 4.52-4.71 (m, 2H), 5.09 (br s, 1H), 4.99-5.03 (m, 1H), 5.10-5.17 (m, 2H), 5.7 (d, J=7.3 Hz, 1H), 7.27-7.38 (m, 5H); 13C NMR (CDCl3) δ 23.66 and 23.76 (2s), 24.82 and 25.04 (2s), 28.88 (s), 37.96 (s), 53.67 and 53.92 (2s), 67.46 and 67.64 (2s), 88.25 and 90.06 (2s), 117.63 and 118.11 (2s), 128.15-128.86 (m, 5C), 134.05 and 134.59 (2s), 137.14 and 137.40 (2s), 156.07 (s); 19F NMR (CDCl3) δ −180.78 (d, J=45.7 Hz, 1F).
trans-2-Allyl-N-benzyloxycarbonyl-3-fluoropiperidine (trans-6d) (polar)
Colorless oil; 1H NMR (CDCl3) δ 1.49-1.64 (m, 2H), 1.72-1.83 (m, 1H), 1.88-2.00 (m, 1H), 2.34-2.44 (m, 2H), 2.77 (t, J=13.3 1H), 3.99 (d, J=13.7 Hz, 1H), 4.55 (dt, J=10.9, 5.3 Hz, 1H), 4.51-4.59 (m, 1H), 4.61-4.70 (m, 1H), 4.98 (d, J=10.0 Hz, 1H), 5.06 (d, J=17.3 Hz, 1H), 5.09-5.16 (m, 2H), 5.70 (d, J=7.32 Hz, 1H), 7.33 (m, 5H); 13C NMR (CDCl3) δ 23.71 (s) 25.68 (s), 28.88 (s), 37.96 (s), 53.67 and 53.92 (2s), 67.46 and 67.64 (2s), 88.25 and 90.06 (2s), 117.63 and 118.11 (2s), 126.11-130.61 (m, 5C), 133.10 (s), 136.36 (s), 156.07 (s); 19F NMR (CDCl3) δ −181.52 (d, J=48.9 Hz, 1F).
2-Allyl-N-benzyloxycarbonyl-3-fluoropyrrolidine (6e) (26% de)
Colorless oil; 1H NMR (CDCl3) δ 1.62-2.40 (m, 4H), 3.16-4.10 (m, 3H), 4.83 (dd, J=52.4, 2.2 Hz, 0.63H), 4.87 (dd, J=52.8, 2.8 Hz, 0.37H), 4.96 and 5.00 (2d, J=3.4 and 3.4 Hz, 1H), 5.02-5.11 (m, 1H), 5.12-5.21 (m, 2H), 5.62-5.92 (m, 1H), 7.27-7.38 (m, 5H); 13C NMR (CDCl3) δ 29.02 and 30.05 (2br s), 31.08 and 31.30 (2s), 44.50 and 44.52 (2s), 61.53 and 63.69 (2br s), 66.88 (s), 90.34 and 91.86 (2s), 117.60 (s), 117.96 (s), 127.78 (s), 127.89 and 127.95 (2s), 128.42 and 128.44 (2s), 133.55 (s), 134.29 and134.31 (2s), 136.79 (s), 154.57 and 154.68 (2s); 19F NMR (CDCl3) δ −186.96 and −187.89 (2br s, 0.63F), −176.07 and −175.46 (2br s, 0.37F) ; IR (neat) 2953, 1701, 1447, 1406, 1340, 1279, 1211, 1179, 1098, 1078, 1053, 959, 735 cm−1. HR-MS [EI (+)]: m/z calcd for C15H18FNO2 [M+] 263.1322, found 263.1313. HPLC YMC-Pack SIL column; 150 mm x 4.6 mmφ; n-hexane/2-propanol 50:1, wavelength 254 nm, flow rate: 1.0 mL/min, retention time: 3.8 min (37%), 5.6 min (63%).
General procedure for the preparation of 2-cyano-3-fluoro-N-protected cyclic amine derivatives 7a-d
The substrate compound 5 (1.0 mmol) and trimethylsilyl cyanide (3.0 mmol) were dissolved in dry CH2Cl2 (3 mL) at −78 oC, under nitrogen atmosphere. 1M TiCl4 in CH2Cl2 (1.1 mmol) was added drop- wise via syringe. The reaction was allowed to warm to room temperature, then quenched with saturated aqueous NaHCO3 (5 mL). The aqueous layer was extracted with CH2Cl2 (3 x 5 mL) and the combined organic layer washed with saturated aqueous NaCl (10 mL) and dried over anhydrous Na2SO4. The organic layer was evaporated in vacuo, which was further purified by column chromatography on silica gel (n-hexane/EtOAc 8:1) as eluent giving a mixture of diastereoisomers compound 7. The same procedure was repeated for BF3·OEt2 and SnCl4.
2-Cyano-3-fluoro-N-methyloxycarbonylpiperidine (7a) (48% de)
Colorless oil; 1H NMR (CDCl3) δ 1.51-1.54 (m, 1H), 1.83-1.92 (m, 2H), 2.10-2.30 (m, 1H), 2.96 (td, J=13.4, 2.7 Hz, 0.74H), 3.05 (br t, J=13.4 Hz, 0.26H), 3.77 (s, 3H), 4.06 (br d, J=12.9 Hz, 0.74H), 4.19 (br d, J=11.2 Hz, 0.26H), 4.42-4.60 (m, 0.74H), 4.85 (br d, J=46.2 Hz, 0.26H), 5.43 and 5.53 (2br s, 1H); 13C NMR (CDCl3) δ 22.31 (s), 25.45 and 27.00 (2s), 40.34 (s), 48.33 and 48.61 (2s), 53.45 (s), 85.80 and 87.63 (2s), 114.21 (s), 154.86 (s); 19F NMR (CDCl3) δ −186.45 (br s, 0.26F), −178.76 (d, J=47.3 Hz, 0.74F); IR (neat) 2959, 1707, 1447, 1404, 1366, 1306, 1261, 1202, 1109, 1042, 980, 932, 903, 869, 733, 702 cm−1. HR-MS [EI (+)]: m/z calcd for C8H11FN2O2 [M+] 186.0805, found 186.0802.
2-Cyano-3-fluoro-N-phenyloxycarbonylpiperidine (7b) (50% de)
Mp 79-81oC; 1H NMR (CDCl3) δ 1.55-1.70 (m, 1H), 1.90-2.05 (m, 2H), 2.15-2.35 (m, 1H), 3.12 and 3.20 (2br s, 1H), 4.22 and 4.34 (2d, J=12.9 and 13.9 Hz, 1H), 4.54-4.72 (m, 0.75H), 4.93 (d, J=45.4 Hz, 0.25H), 5.56 (d, J=10.4 Hz, 0.25H), 5.65 (d, J=5.6 Hz, 0.75H), 7.10-7.17 (m, 2H), 7.22-7.29 (m, 1H), 7.36-7.33 (m, 2H); 13C NMR (CDCl3) δ 25.46 and 25.66 (2s), 27.03 and 27.21 (2s), 41.11 (br s), 48.72 (br s), 84.69 and 86.56 (2s), 114.39 (s), 121.43-121.77 (m, 2C), 125.97-126.25 (m), 129.46-129.72 (m, 2C), 151.06 and 151.19 (2s), 152.04 (s); 19F NMR (CDCl3) δ −186.20 and −186.19 (2s, 0.25F), −179.65 (br d, J=45.6 Hz, 0.75F); IR (neat) 2959, 1717, 1593, 1494, 1456, 1408, 1348, 1252, 1196, 1070, 1026, 974, 872, 733 cm−1. HR-MS [EI (+)]: m/z calcd for C13H13FN2O2 [M+] 248.0961, found 248.0960.
N-Benzyloxycabonyl-2-cyano-3-fluoropiperidine (7d) (50% de)
Colorless oil; 1H NMR (CDCl3) δ 1.43-2.04 (m, 4H), 3.08 (t, J=13.5 Hz, 0.25H), 3.16 (t, J=10.8 Hz, 0.75H), 3.83 (d, J=12.9 Hz, 0.25H), 3.94 (d, J=12.5 Hz, 0.75H), 4.45-4.55 (m, 0.25H), 4.66 (d, J=46.8 Hz, 0.75H), 5.14 (s, 2H), 5.77 (d, J=2.8 Hz, 0.75H), 5.91 (s, 0.25H), 7.34 (s, 5H); 13C NMR (CDCl3) δ 18.60 (s), 22.81 and 23.73 (2s), 37.93 (s), 38.59 (s), 67.55 and 67.69 (2s), 85.85 and 87.56 (2s), 127.98 (s, 2C), 128.07 (s), 128.23 and 128.31 (2s), 128.64 (s, 2C), 136.32 and 136.43 (2s), 154.89 (s); 19F NMR (CDCl3) δ −189.83 (t, J=48.8 Hz, 0.75F), −183.46 (d, J=44.3 Hz, 0.25F); IR (neat) 2959, 1701, 1414, 1344, 1312, 1254, 1155, 1047, 974, 874, 731 cm−1. HR-MS [EI (+)]: m/z calcd for C14H15FN2O2 [M+] 262.1118, found 262.1120.
Further purification of a mixture of cis- and trans-7d by PTLC afforded cis-7d and trans-7d.
cis-N-Benzyloxycabonyl-2-cyano-3-fluoropiperidine (cis-7d) (less polar)
Colorless oil; 1H NMR (CDCl3) δ 1.42-1.61 (m, 1H), 1.76-1.95 (m, 2H), 2.09-2.27 (m, 1H), 2.97 (td, J=13.3, 2.7 Hz, 1H), 4.09 (br d, J=13.2 Hz, 1H), 4.42-4.60 (m, 1 H), 5.17 (s, 2H), 5.55 (br s, 1H), 7.32-7.38 (m, 5H); 13C NMR (CDCl3) δ 19.62 (s), 27.76 (s), 35.45 (s), 39.30 (s), 58.08 and 58.63 (2s), 67.87 (s), 87.57 (s), 118.62 (s), 128.49 (s, 2C), 128.60 (s), 129.16 (s), 134.37 and 137.76 (2s), 156.79 (s); 19F NMR (CDCl3) δ −183.40 (d, J=47.0 Hz, 1F).
trans-N-Benzyloxycabonyl-2-cyano-3-fluoropiperidine (trans-7d) (polar)
Colorless oil; 1H NMR (CDCl3) δ 1.49-1.59 (m, 2H), 1.87-2.04 (m, 2H), 3.07 (t, J=12.5 Hz, 1H), 4.21 (br d, J=12.2 Hz, 1H), 4.86 (d, J=45.4 Hz, 1H), 5.20 (s, 2H), 5.47 (br s, 1H), 7.35 (s, 5H); 13C NMR (CDCl3) δ 18.29 (s), 20.78-26.17 (m, 2C), 28.54-28.97 (m), 35.65-40.83 (m), 67.01-67.52 (m), 85.56 (s), 125.31-131.34 (m, 5C), 133.93-138.02 (m), 152.89-157.42 (m); 19F NMR (CDCl3) δ −188.84 (d, J=47.3 Hz, 1F).
Preparation of methyl N-benzyloxycarbonyl-cis-4-fluoro-L-prolinate (10)
N-Benzyloxycarbonyl-trans-4-hydroxy-L-prolinate (9) was prepared from trans-4-hydroxy-L-proline according to literature method in quantitative yield.17,24 Compound 9 was transformed into N-benzyloxycarbonyl-cis-4-fluoro-L-prolinate 10 according to literature method using XtalFluor-E 8 in 82% yield.25
Methyl N-benzyloxycarbonyl-cis-4-fluoro-L-prolinate (10)
[α]D27 −45.0 (c 1.78, CH2Cl2).
Procedure for electrochemical oxidation of 10
The substrate (1.0mmol) and Et4NBF4 (0.1 mmol) were placed in a beaker type cell containing a stirring bar. MeOH and MeCN (1:4) were added and the mixture stirred at 0 oC. The graphite anode and platinum cathodes were fitted and 2.7 Fmol-1 of current was passed through. The reaction mixture was evaporated to eliminate methanol. Water was added and the mixture was then extracted with EtOAc and the combined organic layer dried using anhydrous MgSO4 and filtered. The solvent was removed in vacuo and the resulting concentrate purified by silica gel chromatography to afford 4-fluoro-5-methoxy-L-prolinate 11 in 74% yield.
Methyl (2S,4S)-N-benzyloxycarbonyl-4-fluoro-5-methoxy-L-prolinate (11)
Yellow oil; 1H NMR (CDCl3) δ 2.23-2.46 (m, 1H), 2.52 (dd, J=18.7, 15.0 Hz, 1H), 3.27-3.95 (m, 6H), 4.50-4.66 (m, 1H), 5.14 (t, J=4.3 Hz, 1H), 5.16-5.23 (m, 2H), 5.27 (t, J=4.3 Hz, 1H), 7.19-7.35 (m, 5H); 13C NMR (CDCl3) δ 29.32 and 29.67 (2s), 36.34-37.87 (m), 51.80 (s), 52.29-53.83 (m), 57.63 and 57.83 (2s), 67.32 and 67.54 (2s), 91.08 and 92.32 (2d, J=356.2 and 356.0 Hz), 127.93-128.82 (m, 5C), 136.55 (s), 154.57 (br s), 171.73 (br s); 19F NMR (CDCl3) δ −173.68 (br s, 1F); IR (neat) 2955, 1755, 1703, 1414, 1348, 1263, 1206, 1167, 1113, 1003, 957, 916, 735 cm−1; HR-MS [EI (+)]: m/z calcd for C15H18FNO5 [M+] 311.1169, found; 305.1167.
Preparation of methyl N-benzyloxycarbonyl -5-allyl-4-fluoro-L-prolinate (12)
To a mixture of 11 (1.0 mmol) and allyltrimethylsilane (3.0 mmol) in dry CH2Cl2 (3 mL) was added dropwise BF3·OEt2 (2.0 mmol) at −78 oC under nitrogen atmosphere. The reaction was allowed to warm to room temperature over 12 h. The reaction mixture was quenched with saturated aqueous NaHCO3 (5 mL). The aqueous layer was extracted with CH2Cl2 (3 x 5 mL) and the combined organic layer washed with saturated aqueous NaCl (10 mL) and dried over anhydrous Na2SO4. The organic layer was evaporated in vacuo, which was further purified by column chromatography on silica gel (n-hexane/EtOAc 2:1) as eluent giving 12.
Methyl (2S,4S)-5-allyl-N-benzyloxycarbonyl-4-fluoro-L- prolinate (12)
Colorless oil; 1H NMR (CDCl3) δ 1.94-3.00 (m, 4H), 3.41-4.20 (m, 4H), 4.44-4.65 (m, 1H), 4.97-5.25 (m, 3H), 5.18 (d, J=11.8 Hz, 1H), 5.35 (d, J=13.4 Hz, 1H), 5.68-5.90 (m, 1H), 7.22-7.47 (m, 5H); 13C NMR (CDCl3) δ 29.66 and 31.76 (2s), 51.48 and 51.78 (2s), 52.10 (s), 58.17 (s), 67.17 (s), 69.67-70.19 (m), 109.73-110.75 (m), 116.82-121.24 (m), 127.43-128.89 (m, 5C), 134.10 (s), 136.50 (s), 160.84 (s), 171.85 (s); 19F NMR (CDCl3) δ −173.63 (br s, 1F); IR (neat) 2953, 1757, 1709, 1436, 1354, 1213, 1175, 957, 756 cm−1; HR-MS [EI (+)]: m/z calcd for C17H20FNO4 [M+] 322.1376, found; 322.1361.
Demethoxycarbonylation of 12
2N NaOH (1mmol) was added to a solution of 12 (1.0 mmol) in MeOH (10 mL) and the mixture refluxed for 2 h. MeOH was removed in vacuo and the pH was adjusted to 1 with 3N HCl. The resulting suspension was extracted using EtOAc (3x 5 mL). The combined organic layer was dried using anhydrous Na2SO4 and evaporated to give the corresponding acid which was further dissolved in MeOH (7 mL). The resulting mixture was placed in a beaker type cell stirring at 0 oC. Then graphite anode and platinum cathode were fitted and 2,6-lutidine (1.2 mmol) was added and a constant current of 2.0 Fmol-1 was passed through. The solvent was evaporated followed by addition of aqueous NaCl (7 mL). The mixture was extracted with EtOAc 3 times and the combined organic layer dried over anhydrous MgSO4 and filtered. The solvent was removed under vacuo to give the corresponding methoxylated compound 14. Triethylsilane (0.75 mmol) was added to a stirred solution of 14 (0.50 mmol) dissolved in dry CH2Cl2 (3 mL) at −78 oC under nitrogen atmosphere. The reaction was allowed to warm to 0 oC for 1 h. Methanesulfonic acid (0.60 mmol) was then added drop wise and the mixture was stirred over 30 min at room temperature. Water (20 mL) was added and the solution was extracted with CHCl3 (3 x 10 mL). The combined organic layer was dried over anhydrous MgSO4 and filtered. The organic layer was evaporated in vacuo and the concentrate was purified by using silica-gel column chromatography (n-hexane/EtOAc 2:1) as eluent giving 13 in 58% yield.
(2R,3S)-2-Allyl-N-benzyloxycarbonyl-3-fluoropyrrolidine (13)
Colorless oil; 1H NMR (CDCl3) δ 1.94-2.90 (m, 4H), 3.25-4.10 (m, 3H), 4.81-4.88 (m, 1H), 4.94-5.50 (m, 4H), 5.62-5.92 (m, 1H), 7.32-7.38 (m, 5H); 13C NMR (CDCl3) δ 29.28 and 30.05 (2br s), 31.52 (s), 44.51 and 44.53 (2s), 61.55 and 63.02 (2br d), 66.91 (s), 89.91-92.87 (m), 117.59 (s), 117.93 (s), 127.80 (s), 127.90 and 127.95 (2s), 128.42 (s), 133.33 (br s), 134.32 (s), 136.81 (s), 154.90 (s); 19F NMR (CDCl3) δ −187.61 and −186.68 (2br s); IR (neat) 2953, 1701, 1447, 1406, 1340, 1279, 1211, 1179, 1098, 1078, 1053, 959, 735 cm−1; HR-MS [EI (+)]: m/z calcd for C15H18FNO2 [M+] 263.1322, found 263.1313. HPLC YMC-Pack SIL column; 150 mm x 4.6 mmφ; n-hexane/2-propanol 50:1, wavelength 254 nm, flow rate: 1.0 mL/min, retention time: 3.8 min (2S, 9%), 5.6 min (2R, 91%).
ACKNOWLEDGEMENTS
This research was supported by a Grant-in-Aid for Scientific Research on Innovative Areas (23105539) from The Ministry of Education, Culture, Sports, Science and Technology, a Grant-in-Aid for Scientific Research (C) (24590012) from The Japan Society for the Promotion of Science, Research Grant for Pharmaceutical Sciences from Takeda Science Foundation, and the President’s Discretion Fund of Nagasaki University.
References
1. Some representative reviews: F. J. Sardina and H. Rapoport, Chem. Rev., 1996, 96, 1825; CrossRef P. D. Bailey, P. A. Millwood, and P. D. Smith, Chem. Commun., 1998, 633; CrossRef S. Laschat and T. Dickner, Synthesis, 2000, 1781; CrossRef A. Mitchinson and A. Nadin, J. Chem. Soc., Perkin Trans. 1, 2000, 2862; CrossRef M. D. Groaning and A. I. Meyers, Tetrahedron, 2000, 56, 9843; CrossRef P. M. Weintraub, J. S. Sabol, J. M. Kane, and D. R. Borcherding, Tetrahedron, 2003, 59, 2953; CrossRef M. G. Buffat, Tetrahedron, 2004, 60, 1701. CrossRef
2. J. L. Castro, I. Collins, M. G. N. Russell, A. P. Watt, B. Sohal, D. Rathbone, M. S. Beer, and J. A. Stanton, J. Med. Chem., 1998, 41, 2667; CrossRef Y. Takeuchi, T. Tarui, and N. Shibata, Org. Lett., 2000, 2, 635; CrossRef P. T. Nyffeler, G. D. Sergio, D. B. Michael, P. V. Stephanne, and W. Chi-Huey, Agnew. Chem. Int. Ed., 2005, 44, 192; CrossRef L. Riyuan, D. Shentao, S. Zhuangzhi, and J. Ning, Org. Lett., 2011, 13, 4498; CrossRef C. Walpole, Z. Liu, E. E. Lee, F. Zhou, N. Mackintosh, M. Sjogren, D. Taylor, J. Shen, and R. A. Batey, Tetrahedron Lett., 2012, 53, 2942. CrossRef
3. D. C. Lankin, N, S. Chandrakumar, S. N. Rao, D. P. Spangler, and J. P. Synder, J. Am. Chem. Soc., 1993, 115, 3356; CrossRef L. Demange, A. Ménez, and C. Dugave, Tetrahedron Lett., 1998, 39, 1169; CrossRef J. P. Synder, N. S. Chandrakumar, H. Sato, and D. C. Lankin, J. Am. Chem. Soc., 2000, 122, 544; CrossRef S. A. Golubev, S. Hartmut, R. Gabor, M. Fioroni, S. Thust, and B. Burger, Tetrahedron Lett., 2004, 45, 1445; CrossRef J. P. Synder, K. Hardcastle, A. Sun, and D. C. Lankin, Chem. Eur. J., 2005, 11, 1579; CrossRef G. Verniest, R. Surmont, E. Van Hende, A. Deweweire, D. Frederik, J. W. Thuring, and N. D. Kimpe, J. Org. Chem., 2008, 73, 5458; CrossRef P. K. Mykhailiuk, S. V. Shishkina, O. V. Shishkin, O. A. Zaporozhets, and I. V. Komarov, Tetrahedron, 2011, 67, 3091; CrossRef P. S. Rajendra and T. Umemoto, J. Org. Chem., 2011, 76, 3113. CrossRef
4. I. Nowak, L. M. Roger, D. R. Rogers, and S. J. Thrasher, J. Fluorine Chem., 1999, 99, 73; CrossRef P. S. Rajendra and M. S. Jean’ne, Acc. Chem. Res., 2004, 37, 31; CrossRef A. Togni and H. Ibrahim, Chem. Commun., 2004, 1147; J. Cossy, P. D. Gomez, and I. Dechamps, Synlett, 2007, 263; CrossRef L. K. Kirk, Org. Proc. Res. Dev., 2008, 12, 305; CrossRef L. Hunter, Beil. J. Org. Chem., 2010, 6, 38; CrossRef T. Furuya, A. S. Kamlet, and T. Ritter, Nature, 2011, 473, 470; CrossRef D. Chopra, Cryst. Growth Des., 2012, 12, 541. CrossRef
5. Some representative reviews: J. M. Moolenaar and N. W. Speckamp, Tetrahedron, 2000, 56, 3817; CrossRef A. Yazici and S. G. Pyne, Synthesis, 2009, 339; CrossRef A. Yazici and S. G. Pyne, Synthesis, 2009, 513. CrossRef
6. T. Shono, Y. Matsumura, K. Tsubata, and K. Uchida, J. Org. Chem., 1986, 51, 2590; CrossRef M. Skrinjar and L.-G. Wistrand, Tetrahedron Lett., 1990, 31, 1775; CrossRef T. Shono, T. Fujita, and Y. Matsumura, Chem. Lett., 1991, 81; CrossRef A. Rouchaud and J.-C. Braekman, Eur. J. Org. Chem., 2011, 12, 2346; CrossRef O. Onomura, Heterocycles, 2012, 85, 2111. CrossRef
7. R. E. Banks, J. Fluorine Chem., 1998, 87, 1; CrossRef Y. Takeuchi, T. Suzuki, A. Satoh, T. Shiragami, and N. Shibata, J. Org. Chem., 1999, 64, 5708; CrossRef A. J. Poss and G. A. Shia, Tetrahedron Lett., 1999, 40, 2673; CrossRef D. Cahard and C. Audouard, Org. Lett., 2000, 2, 3699; CrossRef B. Greedy and V. Gouverneur, Chem. Commun., 2001, 233; CrossRef S. Mizuta and O. Onomura, RSC. Adv., 2012, 2, 2266; S. Singh, C.-M. Martinz, S. Calvet-Vitale, A. K. Prasad, T. Prangé, P. I. Dalko, and H. Dhimane, Synlett, 2012, 23, 2421. CrossRef
8. T. Shono, H. Hamaguchi, and Y. Matsumura, J. Am. Chem. Soc., 1975, 97, 4264. CrossRef
9. T. Shono, Y. Matsumura, T. Tsubata, Y. Sugihara, S. Yamane, T. Kanazawa, and T. Aoki, J. Am. Chem. Soc., 1982, 104, 6697. CrossRef
10. Electrophilic chlorination and bromination of 4: T. Shono, Y. Matsumura, O. Onomura, M. Ogaki, and T. Kanazawa, J. Org. Chem., 1987, 52, 536. CrossRef
11. A. Alix, C. Lalli, P. Retailleau, and G. Masson, J. Am. Chem. Soc., 2012, 134, 10389. CrossRef
12. For deoxofluorination: R. P. Singh and J. M. Shreeve, Synthesis, 2002, 2561; CrossRef F. Beaulieu, L.-P. Beauregard, G. Courchesne, M. Couturier, F. Laflamme, and A. L’Heureux, Org. Lett., 2009, 11, 5050; CrossRef A. L’Heureux, F. Beaulieu, C. Bennet, D. R Bill, S. Clayton, F. Laflamme, M. Mirmehrabi, S. Tadayon, D. Tovell, and M. Couturier, J. Org. Chem., 2010, 75, 3401. CrossRef
13. O. Onomura, P. G. Kirira, T. Tanaka, S. Tsukada, Y. Matsumura, and Y. Demizu, Tetrahedron, 2008, 64, 7498; CrossRef P. G. Kirira, M. Kuriyama, and O. Onomura, Chem. Eur. J., 2010, 16, 3970; CrossRef S. Hirata, M. Kuriyama, and O. Onomura, Tetrahedron, 2011, 67, 9411. CrossRef
14. C. Bucher, C. Sparr, W. B. Schweizer, and R. Gilmour, Chem. Eur. J., 2009, 15, 7637; CrossRef L. E. Zimmer, C. Sparr, and R. Gilmour, Angew. Chem. Int. Ed., 2011, 50, 2. CrossRef
15. BF3·OEt2 mediated allylation of 3-chloro-2-methoxy-N-benzyloxycarbonylpiperidine gave 2-allyl-3-chloro-N-benzyloxypiperidine in 87% de and 74% yield.
2-Allyl-3-chloro-N-benzyloxypiperidine: Colorless oil; 1H NMR (CDCl3) δ 1.45-1.51 (m, 1 H), 1.90-1.99 (m, 1H), 2.03-2.09 (m, 2H), 2.29-2.34 (m, 1H), 2.39-2.46 (m, 1H), 2.87 (br t, J=13.2 Hz, 1H), 4.15-4.21 (m, 2H), 4.57 (br t, J=7.7 Hz, 1H), 5.03-5.10 (m, 2H), 5.15 (s, 2H), 5.65-5.78 (m, 1H), 7.28-7.35 (m, 5H); 13C NMR (CDCl3) δ 18.99 (s), 27.13 (s), 34.81 (s), 38.64 (s), 53.32 (s), 57.41 and 57.95 (2s), 67.18 (s), 117.87 (s), 127.72, 127.84 and 128.40 (3s, 5C), 133.60 (s), 136.98 (s), 155.99 (s); IR (neat) 2951, 1692, 1423, 1348, 1246, 1186, 1123, 1026, 916, 733 cm−1. HR-MS [EI (+)]: m/z calcd for C16H20ClNO2 [M+] 293.1183, found; 293.1174. HPLC YMC-Pack SIL column; 150 mm x 4.6 mmφ; n-hexane/2-propanol 50:1, wavelength 254 nm, flow rate: 1.0 mL/min, retention time: 2.7 min (6.3%), 3.5 min (93.7%).
16. M. Köck, J. Junker, and T. Lindel, Org. Lett., 1999, 1, 2041; CrossRef M. Perez-Trujillo, P. Nolis, and T. Parella, Org. Lett., 2007, 9, 29. CrossRef
17. J. E. Baldwin, S. J. Bamford, A. M. Fryer, and M. E. Wood, Tetrahedron Lett., 1995, 36, 4869; CrossRef J. E. Baldwin, S. J. Bamford, A. M. Fryer, M. P. W. Rudolph, and M. E. Wood, Tetrahedron, 1997, 53, 5233. CrossRef
18. Some literature for fluorinated cyclic amines: L. Demange, J. Cluzeau, A. Ménez, and C. Dugave, Tetrahedron Lett., 2001, 42, 651; CrossRef A. S. Golubev, H. Schedel, G. Radics, M. Fioroni, S. Thust, and K. Burger, Tetrahedron Lett., 2004, 45, 1445. CrossRef
19. Using 1.1 equiv of Lewis acids lowered the yields of allylated products 12 and 13.
20. L. Franck, C. Sylvain, B. Pascal, and G. Courdet, Tetrahedron, 2001, 57, 6969. CrossRef
21. L. E. Burgess, K. M. G. Elizabeth, and J. Jurka, Tetrahedron Lett., 1996, 37, 3255. CrossRef
22. O. Okitsu, R. Suzuki, and S. Kobayashi, J. Org. Chem., 2001, 66, 809. CrossRef
23. S. Furukubo, N. Moriyama, O. Onomura, and Y. Matsumura, Tetrahedron Lett., 2004, 45, 8177. CrossRef
24. W. Maison, E. Arce, P. Renold, R. J. Kennedy, and D. S. Kemp, J. Am. Chem. Soc., 2001, 123, 10245. CrossRef
25. R. P. Singh and T. Umemoto, J. Org. Chem., 2011, 76, 3113. CrossRef