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A Comparison between KBH4 and NaBH4 in Their Reduction of Pyridinium Salts
This paper compares potassium borohydride and sodium borohydride in the reduction of pyridinium salts to tetrahydropyridines. The results indicate that potassium borohydride is more suitable for this reaction with low costs, mild reaction conditions and improved yields. Tetrahydropyridines are an important category of heterocyclic compounds with various biological activities and medicinal value. They are widely found in natural products and synthetic drugs. More importantly, tetrahydropyridines can be easily hydrogenated to afford piperidines, which are widely-used synthetic building blocks. Although various metal catalysts have been reported for the reduction of pyridines to piperidines, these catalysts are generally expensive and reaction conditions are also very harsh. Therefore, an indirect synthetic strategy from pyridinium salts is a good alternative (Figure 1). Since Panouse and Lyle reported the reduction of pyridinium salts with potassium borohydride and sodium borohydride, this methodology have been widely used and reported. Figure 1. General synthetic route to piperidine derivative Sodium borohydride was used in most cases as the reducing reagent to reduce pyridinium salts, while in a few reports potassium borohydride was used as the reducing reagent. In addition, the solvents were either methanol or ethanol. Seemingly, these synthetic protocols were well-established, since the reported yields were generally very good and the reaction conditions were very mild. Recently, we have to prepare 1-benzyl-4-(3-nitrophenyl)-1,2,3,6-tetrahydropyridine (1a) in multi-gram scale. When we first followed a common protocol (NaBH4/MeOH), moderate yields were obtained. Thus, an optimization was then attempted. As a result, we found out a subtle distinction between sodium borohydride and potassium borohydride in this reduction, which has not yet been systematically revealed. Herein, we report the details of our investigation. Our synthesis of 1-benzyl-4-(3-nitrophenyl)-1,2,3,6-tetrahydropyridine (1a) was shown in Scheme 1. The compound 2a, prepared from pyridine-4-boronic acid, was treated with benzyl bromide to give the pyridinium salt 3a in an 84% yield. Since sodium borohydride was most often used in this reduction, it was naturally first used as the reducing reagent. Scheme 1. Reagents and conditions: (a) benzyl bromide (1.2 eq.), acetone, 60 °C, 84%; (b) KBH4 (3.0 eq.), MeOH, -5 °C, 89%. When the reaction was conducted at room temperature in methanol, a moderate yield was obtained (Table 1, entry 1). At room temperature, sodium borohydride in itself could react violently with methanol. In addition, a small amount of 4 was also produced as a major impurity. These results could be ascribed to the relatively high activity of sodium borohydride. When the temperature was lowered to -5 °C, the reaction of sodium borohydride with methanol could be effectively restrained and the yield of 1a was increased to 71% (Table 1, entry 2). Nevertheless, we still hoped to further optimize the reaction conditions. Therefore, NaBH(OAc)3 was attempted as a reducing reagent. But its reducing activity was too low to effect this reduction (Table 1, entry 7). Finally, potassium borohydride was found out to be the best reducing reagent. It was slightly less active than NaBH4. Potassium borohydride could reduce the pyridinium salt 3a smoothly, while it did not react violently with methanol in itself. The yield could be improved to 89%, when the reaction was conducted at -5 °C in methanol (Table 1, entry 5). Moreover, the results indicated that methanol and lower temperature was better than ethanol and higher temperature (Table 1, entries 4-6). Table 1. The optimization of the reduction of 3a Entry Reducing reagent solvent T (°C) T (h) Yield (%) 1 NaBH4 MeOH 20 2.0 62 2 NaBH4 MeOH -5 4.5 71 3 NaBH4 EtOH -5 6.0 52 4 KBH4 MeOH 20 2.0 78 5 KBH4 MeOH -5 4.5 89 6 KBH4 EtOH -5 5.0 63 7 NaBH(OAc)3 MeOH -5 4.5 _ [a] Isolated yield [b] No products obtained To explore the universality of the protocol, a series of pyridinium salts were prepared and subjected to the reduction with potassium borohydride and sodium borohydride, respectively. The results are summarized in Table 2. The detailed synthesis of these pyridinium salts can be seen in the supporting information. It can be seen that the yield of potassium borohydride was generally higher than that of sodium borohydride. This protocol was especially useful for those compounds bearing nitroor cyanogroups, since more impurities might be produced, resulting in lower yields, when sodium borohydride was the reducing reagent. Table 2. A comparison between KBH4 and NaBH4 Entry R R X Product Yield (%) Yield (%) 1 H benzyl Br 1b 92 82 2 methyl benzyl Br 1c 90 80 3 methyl 4-nitrobenzyl Br 1d 89 73 4 3-nitrophenyl 4-nitrobenzyl Br 1e 84 63 5 4-cyanophenyl benzyl Br 1f 90 67 6 4-nitrophenyl allyl Br 1g 86 72 7 4-nitrophenyl methyl I 1h 87 77 [a] Isolated yield using KBH4 as reducing reagent [b] Isolated yield using NaBH4 as reducing reagent In conclusion, we studied the reduction conditions of pyridinium salts and compared potassium borohydride and sodium borohydride in this reaction. The potassium borohydride was preferable to sodium borohydride with better yields. This method was inexpensive, convenient and potential for industrial productions. EXPERIMENTAL Commercial reagents were used without further purification. Melting points were measured on a SGW X-4 (INESA) melting point apparatus and are uncorrected. H NMR spectra were recorded on a Bruker DRX500 (500 MHz) instrument. C NMR spectra were obtained on a JNMEX400 (125 MHz) instrument. Mass spectra (MS) were determined on a Bruker MicroTof II mass spectrometer or a Waters High Resolution UPLCTOFMS spectrometer. IR spectra were obtained using ATR on the FTIR Bruker Tensor 27. General procedure for the reduction of pyridinium salts. All reduction reactions were run on the multi-gram scale, using the following general procedure. 1-Benzyl-4-(3-nitrophenyl)-1,2,3,6-tetrahydropyridine (1a). To a solution of compound 3a (1.0 g, 2.7 mmol) in MeOH (10 mL) at -5 °C was added KBH4 (0.44 g, 8.1 mmol) slowly. The resulting mixture was stirred at -5 °C for 4.5 h. The reaction was quenched with acetaldehyde solution (40% aqueous solution, 2.7 g, 24.3 mmol). The mixture was then filtered and filtrate was evaporated to dryness. The residue was extracted with CH2Cl2 (3 × 10 mL) and washed with water (30 mL). The organic layer was dried over anhydrous Na2SO4, and concentrated. The crude product was purified by column chromatography on silica gel (petroleum ether : EtOAc, 5 : 1) to provide 1a as a yellow solid (0.70 g, 89%). mp 51–53 °C. H NMR (500 MHz, CDCl3) δ 8.26 (t, J = 1.9 Hz, 1H), 8.10 (dd, J = 8.1, 1.5 Hz, 1H), 7.72 (d, J = 7.9 Hz, 1H), 7.50 (t, J = 8.0 Hz, 1H), 7.42 – 7.36 (m, 4H), 7.32 –7.28 (m, 1H), 6.26 – 6.24 (m, 1H), 3.69 (s, 2H), 3.25 – 3.23 (m, 2H), 2.79 (t, J = 5.6 Hz, 2H), 2.62 (br, 2H); LRMS (ESI) m/z (%): 295 (100) [M + H]. 1-Benzyl-1,2,3,6-tetrahydropyridine (1b). General procedure was followed, 3b (4.0 mmol scale). The crude product was purified by column chromatography on silica gel (CH2Cl2) to provide 1b as a liquid (0.64 g, 92%). H NMR (500 MHz, CDCl3) δ 7.29 – 7.23 (m, 4H), 7.19 – 7.16 (m, 1H), 5.70 – 5.66 (m, 1H), 5.61 – 5.57 (m, 1H), 3.51 (s, 2H), 2.91 – 2.89 (m, 2H), 2.49 (t, J = 5.7 Hz, 2H), 2.11 – 2.08 (m, 2H); LRMS (ESI) m/z (%): 174 (100) [M + H]. 1-Benzyl-4-methyl-1,2,3,6-tetrahydropyridine (1c). General procedure was followed, 3c (7.6 mmol scale). The crude product was purified by column chromatography on silica gel (CH2Cl2) to provide 1c as a liquid (1.28 g, 90%). H NMR (500 MHz, CDCl3) δ 7.39 – 7.32 (m, 4H), 7.29 – 7.26 (m, 1H), 5.40 – 5.38 (m, 1H), 3.60 (s, 2H), 2.97 – 2.96 (m, 2H), 2.58 (t, J = 5.8 Hz, 2H), 2.10 (br, 2H), 1.70 (br, 3H); LRMS (ESI) m/z (%): 188 (100) [M + H]. 1-(4-Nitrobenzyl)-4-methyl-1,2,3,6-tetrahydropyridine (1d). General procedure was followed, 3d (3.9 mmol scale). The crude product was purified by column chromatography on silica gel (CH2Cl2) to provide 1d as a yellow solid (0.80 g, 89%). mp 72–74 °C; H NMR (500 MHz, CDCl3) δ 8.17 (d, J = 8.7 Hz, 2H), 7.53 (d, J = 8.6 Hz, 2H), 5.37 – 5.35 (m, 1H), 3.65 (s, 2H), 2.95 – 2.94 (m, 2H), 2.56 (t, J = 5.8 Hz, 2H), 2.08 (br, 2H), 1.69 (br, 3H); C NMR (125 MHz, CDCl3) δ 147.1, 146.6, 132.8, 129.5, 123.5, 118.9, 61.9, 52.9, 50.1, 30.7, 22.9; HRMS (ESI): m/z calcd. for C13H17N2O2 [M + H] : 233.1285; found: 233.1295; IR (ATR): 2795, 1511, 1343, 1112 cm. 1-(4-Nitrobenzyl)-4-(3-nitrophenyl)-1,2,3,6-tetrahydropyridine (1e). General procedure was followed, 3e (3.6 mmol scale). The crude product was purified by column chromatography on silica gel (petroleum ether : CH2Cl2, 1 : 10) to provide 1e as a yellow solid (1.02 g, 84%). mp 100–102 °C; H NMR (500 MHz, CDCl3) δ 8.23 – 8.18 (m, 3H), 8.09 – 8.07 (m, 1H), 7.70 (d, J = 7.9 Hz, 1H), 7.57 (d, J = 8.6 Hz, 2H), 7.48 (t, J = 8.0 Hz, 1H), 6.23 – 6.21 (m, 1H), 3.75 (s, 2H), 3.23 – 3.22 (m, 2H), 2.77 (t, J = 5.6 Hz, 2H), 2.61 (br, 2H); C NMR (125 MHz, CDCl3) δ 148.45, 147.27, 146.12, 142.18, 133.28, 130.74, 129.50, 129.26, 124.27, 123.63, 121.83, 119.69, 61.62, 53.14, 49.84, 27.85; HRMS (ESI): m/z calcd. for C18H18N3O4 [M + H] : 340.1292; found: 340.1290; IR (ATR): 2813, 1511, 1343, 1112 cm. 1-Benzyl-4-(4-cyanophenyl)-1,2,3,6-tetrahydropyridine (1f). General procedure was followed, 3f (2.8 mmol scale). The crude product was purified by column chromatography on silica gel (petroleum ether : EtOAc, 1 : 1) to provide 1f as a yellow solid (0.70 g, 90%). mp 85–87 °C. H NMR (500 MHz, CDCl3) δ 7.62 – 7.61 (m, 2H), 7.49 – 7.48 (m, 2H), 7.41 – 7.35 (m, 4H), 7.32 – 7.28 (m, 1H), 6.24 – 6.23 (m, 1H), 3.68 (s, 2H), 3.24 – 3.22 (m, 2H), 2.76 (t, J = 5.7 Hz, 2H), 2.58 (br, 2H); LRMS (ESI) m/z (%): 275 (100) [M + H]. 1-Allyl-4-(4-nitrophenyl)-1,2,3,6-tetrahydropyridine (1g). General procedure was followed, 3g (3.1 mmol scale). The crude product was pu
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