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Sep 21, 2017 - examples for aliphatic nitriles including benzyl cyanide as the substrates were reported, and low to moderate yields were obtained.8 A ...
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Cite This: J. Org. Chem. 2017, 82, 10939-10944

Catalyst-Dependent Selective Hydrogenation of Nitriles: Selective Synthesis of Tertiary and Secondary Amines Yasunari Monguchi,*,§ Masahiro Mizuno, Tomohiro Ichikawa, Yuki Fujita, Eri Murakami, Tomohiro Hattori,† Tomohiro Maegawa,∥ Yoshinari Sawama, and Hironao Sajiki* Laboratory of Organic Chemistry, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu 501-1196, Japan S Supporting Information *

ABSTRACT: In the presence of palladium on carbon (Pd/C) as a catalyst, hydrogenation of aliphatic nitriles in cyclohexane efficiently proceeded at 25−60 °C under ordinary hydrogen gas pressure to afford the corresponding tertiary amines. However, the use of rhodium on carbon (Rh/C) led to the highly selective generation of secondary amines. Hydrogenation of aromatic nitriles and cyclohexanecarbonitrile selectively produced secondary amines in the presence of either Pd/C or Rh/C.

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INTRODUCTION Transition metal-catalyzed hydrogenation of nitriles has been recognized as a simple method to synthesize amines, which are key functionalities in various organic compounds including biologically active compounds and medicines. However, one of the serious issues with this method is the generation of a mixture of primary, secondary, and tertiary amines without selectivity.1 Recently, several hydrogenation methods for the selective preparation of primary amines from nitriles by the use of ruthenium,2 iron,3 cobalt,4 palladium,5 and palladium−nickel alloy6 catalysts have been developed. In contrast, a relatively limited number of methods have been reported for the selective hydrogenation of nitriles toward secondary or tertiary amines.7−10 Berk et al. reported that a rhenium-catalyzed hydrogenation of aromatic nitriles and cyclohexanecarbonitrile at 140 °C under 75 bar hydrogen pressure selectively afforded the corresponding secondary amines, where the corresponding tertiary amine was majorly formed only from benzyl cyanide with 85% selectivity.7 Liu et al. developed a synthetic method for the preparation of secondary amines by cobalt-catalyzed transfer hydrogenation of benzonitriles using ammonia borane as a hydrogen donor in hexafluoro-2-propanol; however, only two examples for aliphatic nitriles including benzyl cyanide as the substrates were reported, and low to moderate yields were obtained.8 A substrate-dependent selective hydrogenation of nitriles was achieved by Wang et al. using palladium on mesoporous graphitic carbon nitride as a catalyst under 0.1−1 MPa hydrogen pressure. Thus, tertiary amines were obtained from aliphatic linear nitriles with 40%−99% conversion, and secondary amines were generated from only cyclohexanecarbonitrile and benzonitrile with 70% and 89% conversion, respectively.9 The solvent depended selective hydrogenation of butyronitrile to n-butylamine was also achieved by the use of cobalt, ruthenium, or platinum on silica gel or Raney cobalt as a © 2017 American Chemical Society

catalyst, while the substrate applicability is completely confined to only butyronitrile.10 We have reported the palladium on carbon (Pd/C)- and rhodium on carbon (Rh/C)-catalyzed selective alkylation of primary aliphatic amines using aliphatic nitriles as alkylating reagents in MeOH under atmospheric hydrogenation conditions to produce the corresponding tertiary and secondary amines, respectively (Scheme 1).11 This study motivated us to develop a Scheme 1. Pd/C- and Rh/C-Catalyzed Selective Alkylations of Primary Amines Using Nitriles as Alkylating Reagents11

catalyst-dependent hydrogenation of nitriles for the selective synthesis of tertiary and secondary amines using commercially available Pd/C and Rh/C.

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RESULTS AND DISCUSSION The hydrogenation of decanenitrile (1a) with 10% Pd/C as a catalyst under a hydrogen atmosphere at 25 °C selectively proceeded in various solvents to afford the corresponding tertiary amine (4a) (Table 1, entries 1−5). In particular, cyclohexane and Et2O were found to be excellent solvents that facilitated complete conversion and 99% selectivity for the formation of 4a within 6 h (entries 1 and 2). The reaction was unaffected by the amount of Received: July 21, 2017 Published: September 21, 2017 10939

DOI: 10.1021/acs.joc.7b01823 J. Org. Chem. 2017, 82, 10939−10944

Article

The Journal of Organic Chemistry

smoothly proceeded at the almost constant speed accompanied with nearly no formation of the corresponding primary and secondary amines (2a and 3a). The reaction was completed around 6 h (entries 1−5), and a further prolonged period of reaction has almost no effect on the product composition and yield. Primary aliphatic nitriles were hydrogenated in cyclohexane to furnish the corresponding tertiary amines (4) with a high selectivity under the Pd/C-catalyzed hydrogenation conditions (1 atm, 25−60 °C) (Table 2, entries 1−6). In the hydrogenation

Table 1. Optimization of Pd/C-Catalyzed Reaction Conditionsa

Table 2. Scope and Limitations of 10% Pd/C-Catalyzed Hydrogenation of Nitrilesa

a

Reaction conditions: 1a (0.5 mmol) and 10% Pd/C (5 mol %) in solvent (0.5 mL) under ambient hydrogen pressure at 25 °C for 6 h. b Determined by 1H NMR analysis. cIsolated yield of 4a. d5% Pd/C (5 mol %) was used as the catalyst instead of 10% Pd/C. e1 mol % of 10% Pd/C was used.

palladium (Pd) loading content on the activated carbon (entry 6, 5% Pd/C; 5 mol%), while the reduction of the usage of Pd metal to 1 mol % (entry 7, 10% Pd/C; 1 mol%) indicated the significant decrease of the conversion yield. The time-course study of 10% Pd/C-catalyzed hydrogenation of decanenitrile (1a) under a hydrogen atmosphere at 25 °C is shown in Figure 1. The conversion of 1a to tridecylamine (4a)

a

Reaction conditions: 1 (0.5 mmol) and 10% Pd/C (5 mol %) in cyclohexane (0.5 mL) under an H2 atmosphere (balloon) at 25 °C. b Determined by 1H NMR analysis. cIsolated yield of 4. dThe reaction was carried out at 60 °C using 7.5 mol % of 10% Pd/C. eA small amount of the unidentified byproducts was detected. fThe reaction was carried out at 40 °C. gIsolated yield of compound 3. hThe reaction was carried at 60 °C in the presence of molecular sieves 13X (30 wt % toward the substrate). i3% of 4-trifluoromethyltoluene was generated.

of cyclohexanecarbonitrile, the corresponding secondary amine (3) was obtained as the major product rather than the expected tertiary amine (4) with 93% selectivity (entry 7). The decrease in the formation ratio of 4 could be attributed to the lower reactivity of dicyclohexylmethylamine (3) resulting from the relative bulkiness around the amino group. Ammonia, which would function as a moderate catalyst poison in the Pd/C-catalyzed hydrogenation,12 might be generated during the reaction. Hence, the next investigation was conducted at 60 °C using molecular sieves (MS 13X) for the removal of ammonia from the reaction medium,11a but the selectivity of 4 was hardly improved (entry 8). The hydrogenation of 4-methylbenzonitrile bearing an electron-donating methyl group on the benzene ring afforded the secondary amine (3) as the sole product with quantitative conversion (entry 9), while a 42:55 mixture of the primary and secondary benzylamine derivatives was obtained together with 3% deaminated trifluoromethyltoluene from 4-trifluoromethylbenzonitrile (entry 10). These results could be rationally

Figure 1. Time-course study of Pd/C-catalyzed hydrogenation. Reaction conditions: 1a (0.5 mmol) and 10% Pd/C (5 mol%) in cyclohexane (0.5 mL) under ambient hydrogen pressure at 25 °C. The ratios were determined by 1H NMR analyses. The yield in parentheses in entry 5 indicates isolated yield of 4a. 10940

DOI: 10.1021/acs.joc.7b01823 J. Org. Chem. 2017, 82, 10939−10944

Article

The Journal of Organic Chemistry explained by the low nucleophilicity of primary and secondary aromatic amines.11a Next, we investigated the use of Rh/C as a catalyst for the hydrogenation of decanenitrile (1a) at 25 °C under atmospheric hydrogen conditions (Table 3). When the reaction was carried

Table 4. Scope and Limitations of 10% Rh/C-Catalyzed Hydrogenation of Nitrilesa

Table 3. Optimization of Rh/C-Catalyzed Reaction Conditionsa

a

Reaction conditions: 1 (0.5 mmol) and 10% Rh/C (5 mol %) in solvent (0.5 mL) at 25 °C for 6 h. bDetermined by 1H NMR analysis. c Isolated yield of compound 3a. d5% Rh/C (5 mol %) was used as the catalyst instead of 10% Rh/C. e1 mol % of 10% Rh/C was used.

out in cyclohexane using 10% or 5% Rh/C (5 mol %), 1a was completely consumed within 6 h to give the corresponding secondary amine (3a) in a highly selective manner, with the ratio of 3a to the tertiary amine (4a) being 98:2 (entries 1 and 6). The use of other solvents such as Et2O, THF, EtOAc, and MeOH decreased the selectivity (entries 2−5). The reduction of the usage of Rh metal to 1 mol % (entry 7, 10% Rh/C; 1 mol %) led to a significant decrease of the conversion yield. A wide variety of nitriles (1), including aliphatic and aromatic nitriles, could be effectively transformed into the corresponding secondary amines (3) under the 10% Rh/C-catalyzed hydrogenation conditions in cyclohexane (1 atm, 25−50 °C) (Table 4, entries 1−10). The formation of a secondary imine was observed in the hydrogenation of 4-cyanotoluene and 4-cyanoanisole (entries 7 and 9), but the yields of the desired secondary amines (3) were significantly improved upon increasing the reaction temperature from 25 °C to 40 or 50 °C, respectively (entries 8 and 10).13 The hydrogenation of 4-trifluoromethylbenzonitrile bearing an electron-withdrawing trifluoromethyl group on the benzene ring was ineffective, and an increase in temperature to facilitate the reduction of the secondary imine led to the inevitable hydrogenation of the aromatic ring (entries 11 and 12).14 The reuse tests of 10% Pd/C and 10% Rh/C were investigated for the hydrogenation of decanenitrile (Table 5); 10% Pd/C and 10% Rh/C were recovered by filtration using a 1 μm filter paper after 6 h of hydrogenation, and the product ratio was determined by a 1H NMR analysis after evaporation to dryness of the filtrate. Although the recovered 10% Pd/C could be reused only once, 10% Rh/C was totally nonreusable. A plausible reaction pathway for the hydrogenation of nitriles (1) is illustrated in Scheme 2 in analogy with the reaction network reported by von Braun.1b The nitrile (1) is initially hydrogenated to the corresponding imine (A), which readily undergoes further hydrogenation to yield a primary amine (2). Further nucleophilic addition of 2 to A and subsequent

a

Reaction conditions: 1 (0.5 mmol) and 10% Rh/C (5 mol %) in cyclohexane (0.5 mL) at 25 °C. bDetermined by 1H NMR analysis. c The total yield of the mixture is indicated. In the case that the isolated yield is not shown in parentheses, 3 was not isolated due to its instability during column chromatography. dIsolated yield of compound 3. eThe reaction was carried out at 40 °C. f81% of the secondary imine was generated. gThe reaction was carried out at 50 °C. h65% of the secondary imine was generated. i8% of the secondary imine was generated. j35% of the secondary imine was generated. k Hydrogenation of the benzene ring of the nitriles and/or amines also proceeded, and the ratio of these materials could not be calculated.

elimination of ammonia gives an N-alkylated imine (5), which is hydrogenated to the corresponding secondary amine (3). Another nucleophilic addition of 3 to A followed by the dissociation of ammonia and subsequent hydrogenation affords the corresponding tertiary amine (4). Then, we confirmed the possibility of the reaction routes by the nucleophilic addition of 3 to 5 using an N-alkylated imine (5b)15 as a model substrate (Scheme 3). When 10% Pd/C was used as the catalyst, the generation of a trace amount of tertiary amine (4b) together with a secondary amine (3b, 76%) was confirmed by 1H NMR. The primary amine (2b), which could be generated by the nucleophilic condensation of 5b with the secondary amine (3b), was not able to be detected because of its volatile nature. These results indicate that the reaction route from 3 and 5 to 4 (dashed line in Scheme 2) is not excluded, although it is a very minor route. However, the use of 10% Rh/C for the reaction of 5b resulted only in the hydrogenation of 5b to 3b, which is equivalent to the result depicted in Table 4, entry 2, i.e., that the 10% Rh/C-catalyzed hydrogenation of hexanenitrile (1b) almost entirely gives the corresponding secondary amines (3b). These results are obviously controlled by the relative stability of the unisolable and short-lived N-nonalkylated imine 10941

DOI: 10.1021/acs.joc.7b01823 J. Org. Chem. 2017, 82, 10939−10944

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The Journal of Organic Chemistry Table 5. Reuse Test of 10% Pd/C and 10% Rh/Ca

in cyclohexane as a solvent led to the selective formation of the corresponding tertiary amines, while secondary amines were obtained from cyclohexanecarbonitrile and 4-methylbenzonitrile. However, the 10% Rh/C-catalyzed hydrogenation of nitriles in cyclohexane selectively gave secondary amines regardless of the structural features of the nitriles. We further revealed that a pathway from an N-alkylated imine and secondary amine to a tertiary amine exists, although it is a minor route. One of the significant features of the reactions reported herein is the use of commercially available catalysts under mild conditions. The methods will be practically applicable for the selective synthesis of tertiary and secondary amines, from the viewpoints of safety and simplicity.

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EXPERIMENTAL SECTION

General. All reagents and solvent were obtained from commercial sources and used without further purification. Pd/Cs and Rh/Cs were obtained from N.E. Chemcat Co. (Tokyo, Japan). The 1H NMR and 13 C NMR spectra were recorded on a JEOL JNM ECA-500 (500 MHz for 1H NMR and 125 MHz for 13C NMR) or AL-400 (400 MHz for 1H NMR and 100 MHz for 13C NMR) spectrometer. CDCl3 was used as the solvent for the NMR measurements. Chemical shifts (δ) were expressed in part per million and internally referenced (0.00 ppm for tetramethylsilane for 1H NMR and 77.0 ppm for 13C NMR for CDCl3). The IR spectra were recorded by a Bruker FT-IR ALPHA. Mass spectra (EI) were taken on a JEOL JMS Q1000GC Mk II Quad GC/MS. Highresolution mass spectra were measured by a Shimadzu hybrid LCMS-ITTOF (LCMS-IT-TOF). Typical Procedure for the 10% Pd/C-Catalyzed Reaction (Table 2). A mixture of the substrate (500 μmol) and 10% Pd/C (26.6 mg, 25.0 μmol) in cyclohexane (0.5 mL) was stirred at 25 °C under an H2 atmosphere (balloon) for a specific time and then passed through a membrane filter (0.2 μm) to remove the catalyst. The catalyst on the filter was washed with EtOAc (20 mL). The filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography. Tri-n-decylamine. See Table 2, entry 1; CAS reg no. 1070-01-5. Trin-decylamine was obtained in 96% yield (70.1 mg, 160 μmol) as a colorless liquid after purification by silica gel column chromatography (hexane/EtOAc = 2:1) from decanenitrile (70.1 mg, 500 μmol): IR (neat) νmax 903.5, 725.1, 649.9; 1H NMR (400 MHz) δ 0.88 (t, 9H, J = 7.0 Hz), 1.27 (m, 42H), 1.42 (m, 6H), 2.39 (t, 6H, J = 7.8 Hz); 13C NMR (100 MHz) δ 14.1, 22.7, 26.8, 27.6, 29.3, 29.6, 29.6, 30.1, 31.9, 54.1; HRMS (LCMS-IT-TOF) m/z [M + H]+ calcd for C30H64N 438.5033, found 438.5033. Tri-n-hexylamine. See Table 2, entry 2; CAS reg no. 102-86-3.16 Trin-hexylamine was obtained in 94% yield (42.2 mg, 157 μmol) after purification by silica gel column chromatography (hexane/EtOAc = 1:2) from n-hexanenitrile (48.6 mg, 500 μmol): 1H NMR (400 MHz) δ 0.89 (t, 9H, J = 7.0 Hz), 1.28−1.31 (m, 18H), 1.41−1.45 (m, 6H), 2.41 (t, 6H, J = 7.8 Hz); 13C NMR (100 MHz) δ 14.1, 22.6, 26.9, 27.4, 31.9, 54.2; HRMS (LCMS-IT-TOF) m/z [M + H]+ calcd for C18H40N 270.3155, found 270.3136. Tri-n-pentylamine. See Table 2, entry 3; CAS reg no. 621-77-2.17 Tri-n-pentylamine was obtained in 98% yield (37.1 mg, 163 μmol) after purification by silica gel column chromatography (hexane/EtOAc = 1:2) from n-pentanenitrile (41.6 mg, 500 μmol): 1H NMR (400 MHz) δ 0.89 (t, 9H, J = 7.0 Hz), 1.20−1.35 (m, 12H), 1.39−1.46 (m, 6H), 2.38 (t, 6H, J = 7.8 Hz); 13C NMR (100 MHz) δ 14.1, 22.7, 26.7, 29.9, 54.2; HRMS (LCMS-IT-TOF) m/z [M + H]+ calcd for C15H34N 228.2686, found 228.2659. Tris(4-phenylbutyl)amine. See Table 2, entry 4. Tris(4phenylbutyl)amine was obtained in 97% yield (66.9 mg, 162 μmol) as a colorless liquid after purification by silica gel column chromatography (CH2Cl2/MeOH = 10:1) from 4-phenylbutyronitrile (72.6 mg, 500 μmol): IR (neat) νmax 649.6, 722.5, 902.6; 1H NMR (500 MHz) δ 1.43− 1.48 (m, 6H), 1.56−1.61 (m, 6H), 2.38 (t, 6H, J = 7.5 Hz), 2.60 (t, 6H, J = 7.75 Hz), 7.15−7.18 (m, 9H), 7.25−7.28 (m, 6H); 13C NMR (125 MHz) δ 26.8, 29.4, 35.9, 53.9, 125.6, 128.2, 128.4, 142.7; HRMS

a

Reaction conditions: 1a (0.5 mmol) and 10% Pd/C or 10% Rh/C (5 mol %) in cyclohexane (0.5 mL) under ambient hydrogen pressure at 25 °C. bDetermined by 1H NMR analysis. cThe formation of insoluble N-decylidene-1-decanamine (5a) was observed in 18% yield as a mixture with 1a, 2a, and 3a.

Scheme 2. Reaction Pathway

Scheme 3. Hydrogenation of Imine 5b

intermediate (A) under 10% Pd/C- or 10% Rh/C-catalyzed reaction conditions. Since the imine (A) is probably more stable under 10% Pd/C-catalyzed hydrogenation conditions in comparison with 10% Rh/C-catalyzed hydrogenation conditions, A could be subjected to nucleophilic attack by not only the primary amine (2) but also the sterically hindered secondary amine (3) to give the corresponding tertiary amine (4) through the route 3 to 4 (Scheme 2) prior to the hydrogenation of A. However, A is unstable under 10% Rh/C-catalyzed hydrogenation conditions, the nucleophilic attack by the relatively bulky secondary amine (3) was nearly completely eliminated; hence, such stability of A toward hydrogenation might lead to an explanation of the difference in selectivity between Pd and Rh.

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CONCLUSION In conclusion, we have developed a catalyst-dependent and highly selective method for the hydrogenation of nitriles. The use of 10% Pd/C for the hydrogenation of primary aliphatic nitriles 10942

DOI: 10.1021/acs.joc.7b01823 J. Org. Chem. 2017, 82, 10939−10944

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The Journal of Organic Chemistry

MHz) δ 14.0, 22.6, 27.6, 30.2, 31.8, 50.2; HRMS (LCMS-IT-TOF) m/z [M + H]+ calcd for C12H28N 186.2216, found 186.2206. Di-n-pentylamine. See Table 4, entry 3; CAS reg no. 2050-92-2.17 Di-n-pentylamine was obtained in 95% yield (37.4 mg, 238 μmol) as a mixture with tri-n-pentylamine (2%, 3.2 μmol) from n-pentanenitrile (41.6 mg, 500 μmol): 1H NMR (400 MHz) δ 0.90 (t, 6H, J = 7.0 Hz), 1.25−1.35 (m, 8H), 1.45−1.52 (m, 4H), 2.59 (t, 4H, J = 7.4 Hz); 13C NMR (100 MHz) δ 14.1, 22.6, 29.6, 29.9, 50.1; HRMS (LCMS-ITTOF) m/z [M + H]+ calcd for C10H24N 158.1903, found 158.1907. Bis(4-phenylbutyl)amine. See Table 4, entry 4. Bis(4-phenylbutyl)amine was obtained in 84% yield (59.1 mg, 210 μmol) as a colorless liquid after purification by silica gel column chromatography (CH2Cl2/ MeOH = 10:1) from 4-phenylbutyronitrile (72.6 mg, 500 μmol): IR (neat) νmax 649.1, 699.2, 723.5, 903.4, 1453.3, 2933.4; 1H NMR (400 MHz) δ 1.52−1.66 (m, 8H), 2.60−2.64 (m, 8H), 7.16−7.19 (m, 6H), 7.22−7.29 (m, 4H); 13C NMR (100 MHz) δ 29.2, 29.5, 35.8, 50.0, 125.7, 128.2, 128.4, 142.4; HRMS (LCMS-IT-TOF) m/z [M + H]+ calcd for C20H27N 282.2216, found 282.2198. Diisoamylamine. See Table 4, entry 5; CAS reg no. 544-00-3. Diisoamylamine was obtained in 100% yield (39.3 mg, 250 μmol) as a colorless liquid without any purification from isopentylnitrile (41.6 mg, 500 μmol): IR (neat) νmax 903.8, 727.5, 649.7; 1H NMR (400 MHz) δ 0.90 (d, 12H, J = 6.8 Hz), 1.36−1.42 (m, 4H), 1.53−1.67 (m, 2H), 2.61 (t, 4H, J = 7.4 Hz); 13C NMR (100 MHz) δ 22.7, 26.2, 39.2, 48.3; HRMS (LCMS-IT-TOF) m/z [M + H]+ calcd for C10H24N 158.1903, found 158.1905. Bis(cyclohexylmethyl)amine. See Table 4, entry 6; CAS reg no. 3309-27-1.19 Bis(cyclohexylmethyl)amine was obtained in 89% yield (46.6 mg, 223 μmol) after purification by silica gel column chromatography (hexane/EtOAc = 1:2) from cyclohexanecalbonitrile (54.6 mg, 500 μmol). Bis(4-methylbenzyl)amine. See Table 4, entry 8; CAS reg no. 9818043-9.20 Bis(4-methylbenzyl)amine was obtained in 82% yield (46.2 mg, 205 μmol) after purification by silica gel column chromatography (hexane/EtOAc = 5:1) from 4-methylbenzonitrile (58.6 mg, 500 μmol). Bis(4-methoxylbenzyl)amine. See Table 4, entry 10; CAS reg no. 122380-12-5.20 Bis(4-methoxylbenzyl)amine was obtained in 90% yield (57.9 mg, 225 μmol) after purification by silica gel column chromatography (hexane/EtOAc = 1:2) from 4-methoxybenzonitrile (66.6 mg, 500 μmol): 1H NMR (400 MHz) δ 1.91 (s, 1H), 3.73 (s, 4H), 3.80 (s, 6H), 6.86 (d, 4H, J = 8.8 Hz), 7.34 (d, 4H, J = 8.8 Hz); 13C NMR (100 MHz) δ 52.3, 55.2, 113.7, 129.3, 132.4, 158.6; HRMS (LCMS-ITTOF m/z [M + H]+ calcd for C16H20NO2 258.1489, found 258.1472. Preparation of N-Hexylidene-1-hexanamine (5b, Scheme 3).22 5b was purified according to the literature.15 n-Hexylamine (506 mg, 5.00 mmol), CuSO4·5H2O (2.5 mg, 10.0 μmol), and H2O (5 mL) were placed in a two-necked glass vessel. To the mixture was dropwise added a 30% aqueous hydrogen peroxide solution (629 μL, 5.00 mmol) at room temperature. After 3.5 h, Et2O (10 mL) and H2O (10 mL) were added to the mixture, and then the layers were separated. The organic layer was washed with H2O (2 × 10 mL) and brine (10 mL), dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo to give Nhexylidenehexan-1-amine in 48% yield (220 mg, 1.20 mmol): 1H NMR (400 MHz) δ 0.87−0.91 (m, 6H), 1.28−1.34 (m, 14H), 1.48−1.60 (m, 4H), 2.20−2.25 (m, 2H), 3.34 (t, 2H, J = 7.2 Hz) 7.62 (m, 1H); 13C NMR (125 MHz) δ 13.9, 14.0, 22.4, 22.5, 25.7, 26.8, 30.7, 31.4, 31.5, 35.7, 61.4, 164.9. Hydrogenation of Imine (5b) (Scheme 3). A mixture of 5b (45.8 mg, 250 μmol) and a catalyst [10% Pd/C (26.6 mg, 25.0 μmol) or 10% Rh/C (25.7 mg, 250 μmol)] in cyclohexane (0.5 mL) was stirred at 25 °C under an H2 atmosphere (balloon) for a specific time and then passed through a membrane filter (0.2 μm) to remove the catalyst. The catalyst on the filter was washed with EtOAc (20 mL). The filtrate was concentrated in vacuo, and then the NMR of the residue was measured.

(LCMS-IT-TOF) m/z [M + H]+ calcd for C30H40N 414.3155, found 414.3128. Triphenethylamine. See Table 2, entry 5; CAS reg no. 97943-53-8.18 Triphenethylamine was obtained in 77% yield (42.4 mg, 129 μmol) after purification by silica gel column chromatography (CH2Cl2/MeOH = 10:1) from phenylacetonitrile (58.6 mg, 500 μmol): 1H NMR (500 MHz) δ 2.76−2.87 (m, 12H), 7.16−7.31 (m, 15H); 13C NMR (125 MHz) δ 33.8, 55.9, 125.9, 128.3, 128.7, 140.5; HRMS (LCMS-IT-TOF) m/z [M + H]+ calcd for C24H28N 330.2216, found 330.2214. Triisoamylamine. See Table 2, entry 6; CAS reg no. 645-41-0. Triisoamylamine was obtained in 100% yield (37.9 mg, 167 μmol) as a colorless liquid without any purification from isoamylnitrile (41.6 mg, 500 μmol): IR (neat) νmax 902.6, 722.9, 649.8; 1H NMR (400 MHz) δ 0.89 (d, 18H, J = 7.2 Hz), 1.29−1.35 (m, 6H), 1.50−1.60 (m, 3H), 2.40 (t, 6H, J = 7.8 Hz); 13C NMR (100 MHz) δ 22.8, 26.6, 35.9, 52.2; HRMS (LCMS-IT-TOF) m/z [M + H]+ calcd for C15H34N 228.2686, found 228.2681. Bis(cyclohexylmethyl)amine. See Table 2, entry 7; Table 2, entry 8; CAS reg no. 3309-27-1.19 For entry 7, bis(cyclohexylmethyl)amine was obtained in 93% yield (48.7 mg, 233 μmol) after purification by silica gel column chromatography (hexane/EtOAc = 1:2) from cyclohexanecarbonitrile (54.6 mg, 500 μmol). For entry 8, bis(cyclohexylmethyl)amine was obtained in 86% yield (45.0 mg, 215 μmol) after purification by silica gel column chromatography (hexane/EtOAc = 1:2) from cyclohexanecarbonitrile (54.6 mg, 500 μmol). MS13X (16.4 mg) was used for the reaction. 1H NMR (400 MHz): δ 0.84−0.93 (m, 4H), 1.09−1.30 (m, 6H), 1.41−1.51 (m, 2H), 1.65−1.80 (m, 10H), 2.41 (d, 4H, J = 6.8 Hz). 13C NMR (100 MHz): δ 26.0, 26.4, 31.4, 37.5, 56.5. HRMS (LCMS-IT-TOF) m/z: [M + H]+ calcd for C14H28N, 210.2216; found, 210.2199. Tris(cyclohexylmethyl)amine. See Table 2, entry 7; Table 2, entry 8; CAS reg no. 3218-01-7.17 For entry 7, tris(cyclohexylmethyl)amine was obtained in 7% yield (3.6 mg, 11.7 μmol) after purification by silica gel column chromatography (hexane/EtOAc = 1:2) from cyclohexanecarbonitrile (54.6 mg, 500 μmol). For entry 8, tris(cyclohexylmethyl)amine was obtained in 11% yield (5.6 mg, 18.3 μmol) after purification by silica gel column chromatography (hexane/EtOAc = 1:2) from cyclohexanecarbonitrile (54.6 mg, 500 μmol). MS13X (16.4 mg) was used for the reaction. 1H NMR (400 MHz): δ 0.73−0.90 (m, 6H), 1.10−1.40 (m, 12H), 1.66−1.79 (m, 15H), 2.01 (d, 6H, J = 6.8 Hz). 13C NMR (100 MHz): δ 26.3, 27.0, 31.9, 36.2, 63.2. HRMS (LCMS-IT-TOF) m/z: [M + H]+ calcd for C21H40N, 306.3155; found, 306.3127. Bis(4-methylbenzyl)amine. See Table 2, entry 9; CAS reg no. 9818043-9.20 Bis(4-methylbenzyl)amine was obtained in 92% yield (51.8 mg, 230 μmol) without any purification from 4-methylbenzonitrile (58.6 mg, 500 μmol): 1H NMR (400 MHz) δ 1.80 (s, 1H), 2.34 (s, 6H), 3.76 (s, 4H), 7.14 (d, 4H, J = 8.0 Hz), 7.22 (d, 4H, J = 8.0 Hz); 13C NMR (100 MHz) δ 21.1, 52.7, 128.1, 129.0, 136.5, 137.2; HRMS (LCMS-ITTOF) m/z [M + H]+ calcd for C16H20N 226.1590, found 226.1579. Typical Procedure for the 10% Rh/C-Catalyzed Reaction (Table 4). A mixture of the substrate (500 μmol) and 10% Rh/C (25.7 mg, 25.0 μmol) in cyclohexane (0.5 mL) was stirred at 25 °C under an H2 atmosphere (balloon) for a specific time and then passed through a membrane filter (0.2 μm) to remove the catalyst. The catalyst on the filter was washed with EtOAc (20 mL). The filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography. Di-n-decylamine. See Table 4, entry 1; CAS reg no. 1120-49-6.19 Din-decylamine was obtained in 86% yield (64.0 mg, 215 μmol) after purification by silica gel column chromatography (hexane/EtOAc = 1:2) from decanenitrile (70.1 mg, 500 μmol): 1H NMR (400 MHz) δ 0.88 (t, 6H, J = 6.8 Hz), 1.26−1.28 (m, 28H), 1.50−1.52 (m, 4H), 2.61 (t, 4H, J = 7.4 Hz); 13C NMR (100 MHz) δ 14.1, 22.7, 27.3, 29.3, 29.51, 29.54, 31.9, 49.8; HRMS (LCMS-IT-TOF) m/z [M + H]+ calcd for C20H44N 298.3468, found 298.3444. Di-n-hexylamine. See Table 4, entry 2; CAS reg no. 143-16-8.21 Di-nhexylamine was obtained in 96% yield (44.5 mg, 240 μmol) as a mixture with tri-n-hexylamine (2%, 3.3 μmol) from n-hexanenitrile (48.6 mg, 500 μmol): 1H NMR (400 MHz) δ 0.88 (t, 6H, J = 7.0 Hz), 1.24−1.29 (m, 12H), 1.44−1.50 (m, 4H), 2.59 (t, 4H, J = 7.4 Hz); 13C NMR (100

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DOI: 10.1021/acs.joc.7b01823 J. Org. Chem. 2017, 82, 10939−10944

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Procedures for reuse tests and 1H and 13NMR spectra of all products (PDF)

(11) (a) Ikawa, T.; Fujita, Y.; Mizusaki, T.; Betsuin, S.; Takamatsu, H.; Maegawa, T.; Monguchi, Y.; Sajiki, H. Org. Biomol. Chem. 2012, 10, 293−304. (b) Sajiki, H.; Ikawa, T.; Hirota, K. Org. Lett. 2004, 6, 4977− 4980. (12) (a) Sajiki, H.; Hirota, K. Chem. Pharm. Bull. 2003, 51, 320−324. (b) Sajiki, H.; Hirota, K. Tetrahedron 1998, 54, 13981−13996. (c) Sajiki, H.; Kuno, H.; Hirota, K. Tetrahedron Lett. 1998, 39, 7127−7130. (d) Sajiki, H. Tetrahedron Lett. 1995, 36, 3465−3468. (13) The use of 10% Pd/C as a catalyst for the hydrogenation of 4cyanoanisole caused a serious deamination of the hydrogenated products to give a mixture including 4-methoxytoluene. (14) For Rh/C-catalyzed hydrogenation of aromatic rings, see: (a) Maegawa, T.; Akashi, A.; Yaguchi, K.; Iwasaki, Y.; Shigetsura, M.; Monguchi, Y.; Sajiki, H. Chem. - Eur. J. 2009, 15, 6953−6963. (b) Hattori, T.; Ida, T.; Tsubone, A.; Sawama, Y.; Monguchi, Y.; Sajiki, H. Eur. J. Org. Chem. 2015, 2015, 2492−2497. (15) Marui, K.; Nomoto, A.; Ueshima, M.; Ogawa, A. Tetrahedron Lett. 2015, 56, 1200−1202. (16) Wetzel, A.; Wöckel, S.; Schelwies, M.; Brinks, M. K.; Rominger, F.; Hofmann, P.; Limbach, M. Org. Lett. 2013, 15, 266−269. (17) Katritzky, A. R.; Yannakopoulou, K.; Lue, P.; Rasala, D.; Urogdi, L. J. Chem. Soc., Perkin Trans. 1 1989, 225−233. (18) Liu, S.; Chen, R.; Deng, G. Chem. Lett. 2011, 40, 489−491. (19) Cui, X.; Dai, X.; Deng, Y.; Shi, F. Chem. - Eur. J. 2013, 19, 3665− 3675. (20) Kumar, R.; Gleißner, E. H.; Tiu, E. G. V.; Yamakoshi, Y. Org. Lett. 2016, 18, 184−187. (21) Lorentz-Petersen, L. L. R.; Jensen, P.; Madsen, R. Synthesis 2009, 24, 4110−4112. (22) Saha, B.; Rahaman, S. M. W.; Daw, P.; Sengupta, G.; Bera, J. K. Chem. - Eur. J. 2014, 20, 6542−6551.

AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Yasunari Monguchi: 0000-0002-2141-3192 Tomohiro Maegawa: 0000-0003-1580-1110 Yoshinari Sawama: 0000-0002-9923-2412 Hironao Sajiki: 0000-0003-2792-6826 Present Addresses §

Laboratory of Organic Chemistry, Daiichi University of Pharmacy, 22-1 Tamagawa-cho, Minami-ku, Fukuoka 8158511, Japan. † Molecular Catalyst Research Center, Chubu University, 1200 Matsumoto-cho, Kasugai, Aichi 487-8501, Japan. ∥ School of Pharmaceutical Sciences, Kinki University, 3-4-1 Kowakae, Higashi-Osaka 577-8502, Japan. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We sincerely thank N.E. Chemcat Co. for the kind gift of Pd/Cs and Rh/Cs. REFERENCES

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DOI: 10.1021/acs.joc.7b01823 J. Org. Chem. 2017, 82, 10939−10944