Hydrogenation of Alkenes with NaBH₄, CH₃CO₂H, Pd/C in the Presence of O- and N-Benzyl Functions

NaBH ₄, CH ₃CO ₂H, Pd/C has been described as an effective reagent system to hydrogenate alkenes. Here, we show that the hydrogenation occurs chemoselectively, making it possible to hydrogenate alkenes under Pd/C catalysis with hydrogen created in situ without O- or N-debenzylation.

• Alkene Hydrogenation
• Benzyl Ether
• Benzyl Ester
• N-Benzyl Group

1. Introduction

One of the most common procedures for the hydrogenation of alkenes in a chemistry laboratory is the hy­drogenation over palladium catalysts such as over palladium on carbon (Pd/C). Because of the danger of working with H₂ in our laboratory, we looked for a reaction system that would generate H₂ in situ. Recently, A. T. Russo et al. [1] [2] have published reaction conditions (NaBH₄, CH₃CO₂H, Pd/C) that would achieve this. We could utilize this system, e.g., in the hydrogenation of 1 to 2 (Scheme 1), where 2 is a precursor to quinines 3 linked to a carrier. At the time, we exchanged the published solvent of the reaction, toluene, to the more easily removable benzene.

One of the common protective groups for the alcohol (OH) function and for the carboxylic acid (CO₂H) function is the benzyl moiety in form of an O-benzyl ether (OCH₂Ph) and O-benzyl ester (CO₂CH₂Ph) [3] . Often, both can be removed by hydrogenolysis when using a palladium on carbon (Pd/C) catalyst [4] . Also, an N-func- tion, such as in an amide, can be protected with a benzyl group, where the group is subsequently removed by Pd-catalysed hydrogenation. Under the conditions of the reductive debenzylation, double bonds can also be

Scheme 1. Olefin hydrogenation with NaBH₄, CH₃CO₂H, Pd/C.

hydrogenated, of course. If the actual desired transformation, however, is to be the hydrogenation of a double bond in the substrate, then one risks losing the benzyl functions as protective groups in the molecule at the same time. Oftentimes, the hydrogenation reaction is not chemoselective, but coincides with the reduction of nitro groups, azide functions, dehalogenations and also with O- and N-debenzylations of O-benzyl ethers and esters, N-benzyl amines and amides. In recent times, more chemoselective catalysts have been developed, mainly based on platinum group metals. These catalysts include polymer-imprinted platinum [5] , ZnX₂-Pd/C and Pt/C systems [6] and platinum sulfides [7] , and specifically prepared Pd-catalysts [8] . Also, the addition of amines [9] [10] or diphenyl sulfide [11] to Pd/C or Pt/C has been found to make the catalysts more chemoselective, where the hydrogenation of alkenes is not accompanied by all of the side reactions mentioned above. With all of the above catalysts available, it is still of importance to develop new chemoselective hydrogenation systems, where the catalysts can be simply prepared.

In the following, the authors show that the reaction system NaBH₄, CH₃CO₂H, Pd/C can be used for the hy­drogenation of alkenes without the loss of O-benzyl or N-benzyl groups, so that benzyl ethers, benzyl esters and N-benzyl amides are not converted concurrently to alcohols, acids, and amides, respectively.

2. Experimental

2.1. Chemicals and Instruments

Melting points were measured on a Stuart SMP 10 melting point apparatus and are uncorrected. Infrared spectra were measured with a Thermo/Nicolet Nexus 470 FT-IR ESP Spectrometer. ¹H and ¹³C NMR spectra were recorded with a Varian 400 NMR (¹H at 395.7 MHz, ¹³C at 100.5 MHz) and a Varian 200 MHz NMR spectrometer (¹H at 200.0 MHz, ¹³C at 50.3 MHz). The chemical shifts are relative to TMS (solvent CDCl₃, unless otherwise noted). Mass spectra were measured with a JMS-01-SG-2 spectrometer. CHN-analysis was performed on a LECO TruSpec Micro instrument. Column chromatography was carried out on silica gel (60 A, 230 - 400 mesh, Sigma-Aldrich).

5w% Palladium on carbon (Aldrich, 205680) was used in all experiments. NaBH₄ and acetic acid were ac­quired commercially. Benzene, toluene and THF were used without prior purification. Benzyl esters 12, 16, 18, 36, and 40 were prepared from the corresponding acids (benzyl alcohol, PPh₃, BrCCl₃, CH₂Cl₂) following a known procedure [12] . Methyl ester 14 was prepared by Wittig olefination from 3-benzyloxy-4-methoxyben- zaldehyde and methoxycarbonylmethylidenetriphenylphosphorane in a minimal amount of CHCl₃. Also, N-benzyl amides 27, 29, 31 and 33 were synthesized from the corresponding acids (benzylamine, PPh₃, BrCCl₃, CH₂Cl₂) [12] . Substituted dibenzyl ethers 38 and 43 were obtained by Wilkinson-type etherification (ArCH₂OH, benzyl chloride, KOH, DMSO) as was 2-benzyloxycinnamaldehyde (24) (2-hydroxycinnamaldehyde, benzyl chloride, KOH, DMSO). 20 and 22 were prepared by Wittig olefination, starting from 2-benzyloxybenzaldehyde and benzoylmethylidenetriphenylphosphorane and from 2-benzyloxycinnamaldehyde (24) and toluoylmethylidenetriphenylphosphorane.

Caution: In the presence of dry palladium on carbon, hydrogen enflames upon contact with air. Therefore, it is advisable to purge the reaction flasks with an inert gas before use in the described hydrogenation. Also, where filtrating the reaction mixture directly, especially when using a paper filter, it must be noted that the filter cake upon drying can enflame due to the fact that unreacted sodium borohydride slowly hydrolyses with air moisture, thereby releasing hydrogen. Therefore, after diligent washing with chloroform, the filter and filter cake should be immersed in water.

2.2. General Procedure for the Hydrogenation of Cinnamates.-Methyl 3-[2-Benzyloxyphenyl]Propionate (13) [ 13 ]

To a solution of methyl o-benzyloxycinnamate (6, 188 mg, 0.70 mmol) in benzene (10 mL) is given Pd/C (70 mg, 5 wt%) and acetic acid (AcOH, 100 mg). Thereafter, is added portionwise NaBH₄ (128 mg, 3.38 mmol). After 3 h at rt, further AcOH (50 mg) and NaBH₄ (60 mg, 1.58 mmol) are added successively, and the resulting mixture is stirred at rt for 12 h. Thereafter, half conc. aq. HCl is added dropwise until there is no futher gas evolution. H₂O (30 mL) is added and the mixture is extracted with CH₂Cl₂ (3 × 20 mL). The combined organic phase is dried over anhydrous MgSO₄, concentrated in vacuo and the residue is subjected to column chromatography on silica gel (CH₂Cl₂) to give 13 (175 mg, 93%) as a colorless oil; ν_max (neat/cm⁻¹) 3064, 3033, 2950, 1736, 1601, 1588, 1493, 1453, 1436, 1381, 1290, 1241, 1193, 1162, 1025, 752; δ_H (400 MHz, CDCl₃) 2.65 (2H, t, ³J = 7.6 Hz), 3.01 (2H, t, ³J = 7.6 Hz), 3.64 (3H, s, OCH₃), 5.09 (2H, s, OCH₂), 6.87 - 6.92 (2H, m), 7.16 - 7.46 (8H, m); δ_C (100.5 MHz, CDCl₃) 26.2 (CH₂), 34.0 (CH₂), 51.5 (OCH₃), 69.7 (OCH₂), 111.5 (CH), 120.7 (CH), 127.0 (2C, CH), 127.6 (CH), 127.8 (CH), 128.6 (2C, CH), 129.1 (C_quat), 130.1 (CH), 137.2 (C_quat), 156.5 (C_quat), 173.8 (C_quat, CO); MS (EI, 70 eV) m/z (%) 270 (M⁺, 85).

2.3. General Procedure for the Hydrogenation of Cinnamides.-N-Benzyl 3-Phenylpropionamide (28) [ 14 ]

To a mixture of N-benzyl cinnamide (335 mg, 1.41 mmol) and Pd/C (70 mg, 5 w%) in toluene (8 mL) was added acetic acid (210 mg) and subsequently NaBH₄ (185 mg). After the mixture was stirred for 14 h, it was filtered, and the filter cake was washed with CHCl₃ (3 × 15 mL). The combined organic phase was concentrated in vacuo, and the residue was subjected to column chromatography on silica gel (ether/CHCl₃/hexane 2:2:1) to give 28 (315 mg, 95%) as a colorless solid, mp. 90˚C - 93˚C; ν_max (KBr/cm⁻¹) 3292 (s, NH), 3061, 3026, 2924, 1639, 1543, 1495, 1453, 1227, 1029, 741, 694; δ_H (400 MHz, CDCl₃) 2.51 (2H, t, ³J = 7.6 Hz), 2.99 (2H, t, ³J = 7.6 Hz), 4.38 (2H, d, ³J = 5.6 Hz), 5.66 (1H, bs, NH), 7.12 - 7.29 (10H, m); δ_C (100.5 MHz, CDCl₃) 31.7 (CH₂), 38.5 (CH₂), 43.6 (CH₂), 126.3 (CH), 127.5 (CH), 127.7 (2C, CH), 128.4 (2C, CH), 128.6 (2C, CH), 128.7 (2C, CH), 138.1 (C_quat), 140.7 (C_quat), 171.9 (C_quat, CO).

2.4. Reduction of Nitro-Containing Compounds―Variant A: Anthranilic Acid Benzyl Ester (41) [ 15 ]

To a mixture of benzyl 2-nitrobenzoate (40, 361 mg, 1.4 mmol), Pd/C (100 mg, 5w%) and AcOH (210 mg) in benzene (10 mL) is slowly added NaBH₄ (185 mg, 4.87 mmol), and the resulting reaction mixture is stirred at rt for 14 h. Thereafter, the mixture is filtrated and the filter cake is washed with CHCl₃ (2 × 20 mL). Column chromatography on silica gel (ether/CH₂Cl₂ 1:10 → ethyl acetate/hexane 1:1) gave 41 (225 mg, 71%) as a pale solid; mp. 75˚C (Lit. 76˚C - 77˚C [15] ); ν_max (KBr/cm⁻¹) 3033, 2950, 1693, 1615, 1487, 1455, 1378, 1291, 1243, 1161; δ_H (400 MHz, CDCl₃) 5.34 (2H, s OCH₂), 6.62 - 6.68 (2H, m), 7.24 - 7.41 (4H, m), 7.44 (2H, d, ³J = 8.8 Hz), 7.93 (1H, d, ³J = 8.0 Hz); δ_H (400 MHz, CDCl₃) 66.0 (OCH₂), 110.7 (C_quat), 116.4 (CH), 116.7 (CH), 128.0 (2C, CH), 128.1 (CH), 128.6 (2C, CH), 131.3 (CH), 134.2 (CH), 136.3 (C_quat), 150.5 (C_quat), 167.9 (C_quat, CO) and 42 (38 mg, 20%).

2.5. Reduction of Nitro-Containing Compounds―Variant B: Anthranilic Acid (42) [ 16 ]

To a mixture of benzyl 2-nitrobenzoate (40, 361 mg, 1.4 mmol), Pd/C (100 mg, 5 w%) and AcOH (210 mg) in benzene (10 mL) is slowly added NaBH₄ (185 mg, 4.87 mmol), and the resulting reaction mixture is stirred at rt for 14 h. Then, additional AcOH (105 mg) and NaBH₄ (100 mg, 2.63 mmol) were added, and the reaction was stirred at rt for an additional 10h. Thereafter, half-conc. aqHCl is added dropwise. Subsequently, water (25 mL) is added, and the mixture is extracted with ethyl acetate (3 × 20 mL). The combined organic phase was dried over anhydrous MgSO₄ and concentrated in vacuo. The residue was subjected to column chromatography on silica gel (ethyl acetate-hexane 1:1) to give anthranilic acid (42, 163 mg, 85%) as a beige-colored solid, mp. 144˚C - 146˚C (Lit. 146˚C - 147˚C [16] ); ν_max (KBr/cm⁻¹) 3472 (NH), 3373 (NH), 3040 - 2350 (bs, OH), 1672, 1617, 1588, 1563, 1485, 1419, 1301, 1247, 1161, 916, 753, 659; δ_H (400 MHz, CDCl₃) 6.65 - 6.69 (2H, m), 7.29 - 7.33 (1H, m), 7.92 (1H, dd, ³J = 8.4 Hz, ⁴J = 1.6 Hz); δ_H (400 MHz, CDCl₃) 109.5 (C_quat), 116.5 (CH), 116.8 (CH), 132.1 (CH), 135.1 (CH), 151.1 (C_quat), 173.1 (C_quat, CO); MS (EI, 70 eV) m/z (%) 137 (M⁺, 64), 119 (100), 92 (81, M⁺-CHO₂).

2.6. Spectral and Analytical Data

Ethyl 3-benzyloxy-4-methoxypropionate (15) [17] . -as a colorless oil; ν_max (neat/cm⁻¹) 1731 (CO), 1515; δ_H (400 MHz, CDCl₃) 1.22 (3H, t, ³J = 7.2 Hz, CH₃), 2.53 (2H, t, ³J = 7.2 Hz), 2.83 (2H, t, ³J = 7.2 Hz), 3.85 (3H, s, OCH₃), 4.09 (2H, q, ³J = 7.2 Hz), 5.11 (OCH₂), 6.73(5) (1H, dd, ³J = 8.4 Hz, ⁴J = 2.0 Hz), 6.74 (1H, d, ⁴J = 2.0 Hz), 6.81 (1H, d, ³J = 8.4 Hz), 7.27 - 7.44 (5H, m); δ_C (100.5 MHz, CDCl₃) 14.2 (CH₃), 30.5 (CH₂), 36.1 (CH₂), 56.1 (OCH₃), 60.4 (OCH₂), 71.0 (OCH₂), 111.8 (CH), 114.4 (CH), 120.8 (CH), 127.3 (2C, CH), 127.8 (CH), 128.5 (2C, CH), 133.1 (C_quat), 137.1 (C_quat), 148.0 (C_quat), 148.1 (C_quat), 173.0 (C_quat, CO); MS (EI, 70 eV) m/z (%) 300 (M⁺, 31).

Benzyl 3-[2-benzyloxyphenyl]propionate (17) [18] .-colorless oil; ν_max (neat/cm⁻¹) 3064, 3033, 2933, 1735, 1601, 1588, 1491, 1450, 1382, 1232, 1110, 1009, 910, 853, 742, 696; δ_H (400 MHz, CDCl₃) 2.71 (2H, t, ³J = 7.6 Hz), 3.05 (2H, t, ³J = 7.6 Hz), 5.09 (4H, s), 6.87 - 6.89 (2H, m), 7.15 - 7.42 (12H, m); δ_C (100.5 MHz, CDCl₃) 26.3 (CH₂), 34.2 (CH₂), 66.1 (OCH₂), 69.7 (OCH₂), 111.6 (CH), 120.8 (CH), 127.0 (2C, CH), 127.6 (CH), 127.7(5) (CH), 128.1 (2C, CH), 128.5 (3C, CH), 128.5(5) (2C, CH), 129.1 (C_quat), 130.1 (CH), 136.1 (C_quat), 137.2 (C_quat), 156.6 (C_quat), 173.2 (C_quat, CO); MS (EI, 70 eV) m/z (%) 346 (M⁺, 73).

Benzyl 3-[4-ethoxyphenyl]propionate (19). -colorless oil; ν_max (KBr/cm⁻¹) 3065, 3033, 2979, 2930 1736, 1612, 1512, 1454, 1383, 1297, 1242, 1150, 1116, 1048, 923, 825, 737, 698; δ_H (400 MHz, CDCl₃) 1.40 (3H, t, ³J = 7.2 Hz), 2.64 (2H, t, ³J = 7.6 Hz), 2.90 (2H, t, ³J = 7.6 Hz), 3.99 (2H, q, ³J = 7.2 Hz, OCH₂), 5.10 (2H, s, OCH₂), 7.29 (2H, d, ³J = 7.6 Hz), 7.34 (2H, d, ³J = 7.6 Hz), 6.79 (2H, d, ³J = 8.8 Hz), 7.08 (2H, d, ³J = 8.8 Hz); δ_C (100.5 MHz, CDCl₃) 14.9 (CH₃), 30.1 (CH₂), 36.2 (CH₂), 63.4 (OCH₂), 66.2 (OCH₂), 114.4 (2C, CH), 128.2 (2C, CH), 128.5 (2C, CH), 129.2 (2C, CH), 132.3 (CH), 135.9 (C_quat), 138.9 (C_quat), 157.5 (C_quat), 172.8 (C_quat, CO); MS (EI, 70 eV) m/z (%) 284 (M⁺, 43).

2-(2’-Benzyloxyphenyl)ethyl phenylketone (21) [19] . -colorless oil; ν_max (KBr/cm⁻¹) 3063, 2929, 1682, 1598, 1495, 1450, 1240, 1111, 1021, 740; δ_H (400 MHz, CDCl₃) 3.09 (2H, t, ³J = 7.2 Hz), 3.27 (2H, dt, ³J = 7.2 Hz, ⁴J = 1.2 Hz), 5.11 (2H, s, OCH₂), 6.89 - 6.95 (2H, m), 7.17 - 7.25 (2H, m), 7.30 - 7.53 (8H, m), 7.90 (2H, d, ³J = 7.6 Hz); δ_C (100.5 MHz, CDCl₃) 26.1 (CH₂), 39.1 (CH₂), 69.9 (OCH₂), 111.6 (CH), 120.9 (CH), 127.3 (2C, CH), 127.5 (CH), 127.9 (CH), 128.1 (2C, CH), 128.5 (2C, CH), 128.6 (2C, CH), 129.8 (C_quat), 130.4 (CH), 132.8 (CH), 136.8 (C_quat), 137.2 (C_quat), 156.6 (C_quat), 200.1 (C_quat, CO); MS (EI, 70 eV) m/z (%) 316 (M⁺, 23).

1-Benzyloxy-2-[4-(4-methylbenzoyl)butyl]benzene (23). -colorless oil; ν_max (KBr/cm⁻¹) 3062, 3032, 2927, 2858, 1680, 1606, 1493, 1451, 1379, 1290, 1238, 1180, 1112, 1025, 752, 696; δ_H (400 MHz, CDCl₃) 1.61 - 1.82 (4H, m), 2.40 (3H, s, CH₃), 2.72 (2H, t, ³J = 7.2 Hz), 2.93 (2H, t, ³J = 7.2 Hz), 5.07 (2H, s, OCH₂), 6.88 - 6.91 (2H, m), 7.13 - 7.44 (9H, m), 7.83 (2H, d, ³J = 8.0 Hz); δ_C (100.5 MHz, CDCl₃) 21.6 (CH₃), 24.3 (CH₂), 29.6 (CH₂), 30.1 (CH₂), 38.3 (CH₂), 69.8 (OCH₂), 111.6 (CH), 120.7 (CH), 126.9 (CH), 127.1 (2C, CH), 127.7 (CH), 128.2 (2C, CH), 128.5 (2C, CH), 129.2 (2C, CH), 130.0 (CH), 131.1 (C_quat), 134.6 (C_quat), 137.5 (C_quat), 143.5 (C_quat), 156.5 (C_quat), 200.2 (C_quat, CO); MS (EI, 70 eV) m/z (%) 328 (M⁺, 17).

3-(2-Benzyloxyphenyl)propionaldehyde (25) [20] . -colorless oil; ν_max (KBr/cm⁻¹) 2929, 1722, 1600, 1493, 1452, 1382, 1238, 1118, 1019, 748; δ_H (400 MHz, CDCl₃) 2.75 (2H, dt, ³J = 7.6 Hz, ⁴J = 1.6 Hz), 3.00 (2H, t, 3J = 7.6 Hz), 5.08 (2H, s), 6.87 - 6.92 (2H, m), 7.13 - 7.20 (2H, m), 7.30 - 7.43 (5H, m), 9.78 (1H, t, ³J = 1.6 Hz); δ_C (100.5 MHz, CDCl₃) 23.5 (CH₂), 43.9 (CH₂), 69.8 (OCH₂), 111.6 (CH), 120.8 (CH), 127.1 (2C, CH), 127.7 (CH), 127.9 (CH), 128.6 (2C, CH), 128.9 (C_quat), 130.1 (CH), 137.1 (C_quat), 156.5 (C_quat), 202.4 (CHO); MS (EI, 70 eV) m/z (%) 240 (M⁺, 13).

3-(2-Benzyloxyphenyl)propan-1-ol (26) [20] . -colorless oil; ν_max (KBr/cm⁻¹) 3351 (broad, OH), 3064, 3033, 2933, 2864, 1600, 1587, 1493, 1452, 1381, 1239, 1041, 910, 751, 696; δ_N (400 MHz, CDCl₃) 1.86 (2H, tt, ³J = 7.2 Hz, ³J = 6.0 Hz, CH₂), 2.78 (2H, t, ³J = 7.2 Hz, CH₂), 3.60 (2H, t, ³J = 6.0 Hz, OCH₂), 5.08 (2H, s, OCH₂), 6.90 - 6.94 (2H, m), 7.15 - 7.20 (2H, m), 7.31 - 7.45 (5H, m); δ_C (100.5 MHz, CDCl₃) 26.0 (CH₂), 33.0 (CH₂), 61.9 (OCH₂), 70.1 (OCH₂), 111.7 (CH), 121.0 (CH), 127.2 (CH), 127.3 (2C, CH), 128.0 (CH), 128.6 (2C, CH), 130.3 (CH), 130.4 (C_quat), 137.0 (C_quat), 156.6 (C_quat); MS (EI, 70 eV) m/z (%) 240 (M⁺, 25).

N-Benzyl 3-(2,5-dimethoxyphenyl)propionamide (30). -as a colorless solid, mp. 154˚C - 155˚C; ν_max (KBr/ cm⁻¹) 3311, 3063, 2948, 2839, 1638, 1593, 1541, 1474, 1255, 1161, 1113, 774; δ_H (400 MHz, CDCl₃) 2.61 (2H, t, ³J = 7.2 Hz), 2.95 (2H, t, ³J = 7.2 Hz), 3.67 (2C, 2 OCH₃), 6.42 (1H, s, NH), 6.48 (2H, d, ³J = 8.4 Hz), 7.13 (1H, dd, ³J = 8.4 Hz, ³J = 8.4 Hz), 7.15 - 7.20 (2H, m), 7.26 - 7.33 (3H, m); δ_C (100.5 MHz, CDCl₃) 18.6 (CH₂), 35.5 (CH₂), 43.7 (CH₂), 55.4 (2C, 2 OCH₃), 103.6 (2C, CH), 116.5 (C_quat), 127.4 (2C, CH), 128.0 (2C, CH), 128.6 (2C, CH), 138.2 (C_quat), 157.9 (2C, C_quat), 173.1 (C_quat, CO); MS (FAB, 3-nitrobenyl alcohol) m/z (%) 300 (MH⁺, 15).

N-Benzyl 3-(3-methoxy-4-propoxyphenyl)propionamide (32). -as a colorless solid; mp. 127˚C; ν_max (KBr/ cm⁻¹) 3292 (NH), 3057, 3028, 2962, 2934, 2874, 1640, 1550, 1515, 1453, 1256, 1227, 1136, 1025, 803, 741, 697; δ_H (400 MHz, CDCl₃) 1.02 (3H, t, ³J = 7.6 Hz, CH₃), 1.85 (2H, qt, CH₂, ³J = 7.6 Hz, ³J = 6.8 Hz), 2.49 (2H, t, ³J = 7.6 Hz, CH₂), 2.92 (2H, t, ³J = 7.6 Hz, CH₂), 3.80 (3H, s, OCH₃), 3.92 (2H, t, ³J = 6.8 Hz, OCH₂), 4.38 (2H, d, ³J = 1.2 Hz, CH₂), 5.69 (1H, bs, NH), 6.69 (1H, dd, ³J = 8.0 Hz, ⁴J = 2.0 Hz), 6.71 (1H, d, ⁴J = 2.0 Hz), 6.76 (1H, d, ³J = 8.0 Hz), 7.24 - 7.31 (5H, m); δ_C (100.5 MHz, CDCl₃) 10.5 (CH₃), 22.5 (CH₂), 31.4 (CH₂), 38.8 (CH₂), 43.6 (NCH₂), 55.9 (OCH₃), 70.5 (OCH₂), 112.1 (CH), 113.0 (CH), 120.2 (CH), 127.5 (CH), 127.7 (2C, CH), 128.7 (2C, CH), 133.3 (C_quat), 138.1 (C_quat), 147.0 (C_quat), 149.3 (C_quat), 172.0 (C_quat, CO); MS (FAB, 3-nitrobenzyl alcohol) m/z (%) 328 (MH⁺, 23).

N-Benzyl 3-benzyloxy-4-methoxyphenylpropionamide (34). -colorless solid, mp. 142˚C - 143˚C; ν_max (KBr/ cm⁻¹) 3301 (bs, NH), 2936, 1644 (C = O), 1514, 1252, 1154, 1133, 1110, 1049, 1016, 698; δ_H (400 MHz, CDCl₃) 2.39 (2H, t, ³J = 7.6 Hz), 2.86 (2H, t, ³J = 7.6 Hz), 3.85 (3H, s, OCH₃), 4.31 (2H, d, ³J = 5.6 Hz), 5.09 (2H, s, CH₂), 5.56 (1H, bs, NH), 6.70 - 6.73 (2H, m), 6.77 (1H, d, ³J = 8.4 Hz), 7.03 - 7.06 (2H, m), 7.22 - 7.39 (8H, m); δ_C (100.5 MHz, CDCl₃) 31.3 (CH₂), 38.6 (CH₂), 43.5 (CH₂), 56.0 (OCH₃), 70.8 (OCH₂), 111.8 (CH), 114.3 (CH), 121.0 (CH), 127.4 (2C, CH), 127.6 (2C, CH), 127.5 (C_quat), 127.7 (CH), 128.5 (3C, CH), 128.6 (2C, CH), 133.0 (C_quat), 137.1 (C_quat), 147.9 (C_quat), 148.1 (C_quat), 172.0 (C_quat, CO); MS (FAB, 3-nitrobenzyl alcohol) m/z (%) 376 (MH⁺, 11).

N-Benzyl 3-hydroxy-4-methoxyphenylpropionamide (35). -colorless solid, mp. 116˚C - 117˚C (Lit. mp. 117 ˚C [21] ); ν_max (KBr/cm⁻¹) 3501 (bs), 3295 (bs), 1636, 1517, 1453, 1276, 1215, 1128, 1024, 862, 805, 696; δ_H (400 MHz, CDCl₃) 2.47 (2H, t, ³J = 7.6 Hz), 2.89 (2H, t, ³J = 7.6 Hz), 3.85 (3H, s, OCH₃), 4.39 (2H, d, 3J = 5.6 Hz, NCH₂), 5.60 (1H, bs, NH), 6.65 (1H, dd, ³J = 8.4 Hz, ⁴J = 2.2 Hz), 6.73 (1H, d, ³J = 8.4 Hz), 6.76 (1H, d, ⁴J = 2.0 Hz), 7.13 - 7.15 (2H, m), 7.24 - 7.30 (3H, m); δ_H (100.5 MHz, CDCl₃) 31.1 (CH₂), 38.6 (CH₂), 43.6 (NCH₂), 56.0 (OCH₃), 110.7 (CH), 114.4 (CH), 120.0 (CH), 127.4 (CH), 127.8 (2C, CH), 128.6 (2C, CH), 133.9 (C_quat), 137.5 (C_quat), 145.1 (C_quat), 145.6 (C_quat), 172.0 (C_quat, CO); MS (FAB, 3-nitrobenzyl alcohol) m/z (%) 286 (MH⁺, 21).

Benzyl 4-aminobenzoate (37) [22] . -colorless needles, mp. 97˚C; ν_max (KBr/cm⁻¹) 3456, 3359, 3223, 2937, 1683, 1632, 1572, 1517, 1436, 1380, 1310, 1278, 1170, 1116, 974, 846, 771, 730, 691; δ_H (400 MHz, CDCl₃) 4.06 (2H, bs, NH₂), 5.31 (2H, s, OCH₂), 6.62 (2H, d, ³J = 8.8 Hz), 7.30 - 7.44 (5H, m), 7.88 (2H, d, ³J = 8.8 Hz); δ_C (100.5 MHz, CDCl₃) 66.1 (OCH₂), 113.8 (2C, CH), 119.6 (C_quat), 128.0 (2C, CH), 128.5 (2C, CH), 131.8 (3C, CH), 136.6 (C_quat), 150.9 (C_quat), 166.5 (C_quat, CO); MS (FAB, 3-nitrobenzyl alcohol) m/z (%) 228 (MH⁺, 10).

3-Aminobenzyl benzyl ether (39) [23] . -as a pale yellow oil; ν_max (KBr/cm⁻¹) 3500 (bs, NH), 3369 (NH), 3029, 2855, 1619, 1493, 1358, 1299, 1068; δ_H (400 MHz, CDCl₃) 4.48 (2H, OCH₂), 4.55 (2H, OCH₂), 6.62 - 6.64 (1H, m), 6.73 - 6.77 (2H, m), 7.14 (1H, dd, ³J = 8.0 Hz, ³J = 8.0 Hz), 7.25 - 7.39 (5H, m); δ_C (100.5 MHz, CDCl₃) 70.0 (OCH₂), 70.1 (OCH₂), 111.5 (CH), 114.5 (CH), 116.2 (CH), 117.6 (CH), 127.8 (2C, CH), 128.4 (2C, CH), 129.3 (CH), 138.3 (C_quat), 139.5 (C_quat), 146.2 (C_quat); MS (FAB, 3-nitrobenzyl alcohol) m/z (%) 214 (MH⁺, 19).

O-Benzyl 2-aminophenol (44) [24] . -slowly crystallizing oil; mp. 36˚C (Lit. mp. 38˚C [24] ) ν_max (KBr/cm⁻¹) 3466, 3378, 3061, 3032, 2927, 2869, 1613, 1504, 1454, 1381, 1276, 1216, 1142, 1042, 1016, 910, 856, 735, 697; δ_H (400 MHz, CDCl₃) 3.60 (2H, bs, NH), 5.09 (2H, s, OCH₂), 6.71 - 6.88 (4H, m), 7.32 - 7.42 (3H, m), 7.45 (2H, d, ³J = 7.6 Hz); δ_C (100.5 MHz, CDCl₃) 70.4 (OCH₂), 112.1 (CH), 115.3 (CH), 118.5 (CH), 125.5 (CH), 127.6 (2C, CH), 128.0 (CH), 128.6 (2C, CH), 136.4 (C_quat), 137.2 (C_quat), 146.5 (C_quat); MS (FAB, 3-nitrobenzyl alcohol) m/z (%) 200 (MH⁺, 11).

2-Aminophenol (45). -colorless solid; mp. 173˚C (Lit. 174˚C [16] ); ν_max (KBr/cm⁻¹) 3377 (NH), 3306 (NH), 1608, 1515, 1475, 1406, 1285, 1271, 900, 751, 745; δ_H (400 MHz, DMSO-d⁶) 4.70 (2H, bs), 6.40 (1H, d, ³J = 7.6 Hz), 6.54 - 6.59 (2H, m), 6.65 (1H, d, ³J = 6.8 Hz), 8.70 (1H, bs, OH); δ_C (100.5 MHz, DMSO-d⁶) 114.5 (2C, CH), 116.5 (CH), 119.5 (CH), 136.4 (C_quat), 144.0 (C_quat); MS (EI, 70 eV) m/z (%) 109 (M⁺,100), 80 (32).

3. Results and Discussion

The reagent system was also noted to be effective in C-Cl dechlorination reactions [25] . However, when we tried to use NaBH₄, CH₃CO₂H, Pd/C in O-debenzylation reactions, the O-debenzylation, e.g. from 3 to 4, did not proceed, even with an excess of reagent (Scheme 2).

This result gave the authors an indication that NaBH₄, CH₃CO₂H, Pd/C could be used as a reaction system that would allow to hydrogenate double bonds in the presence of benzyl ethers and benzyl esters. The following describes hydrogenations of alkenes carrying O-benzyl ether, O-benzyl ester and N-benzyl amide functions with this reducing agent.

When a finely ground powder of NaBH₄ is added to a mixture of alkene, acetic acid and Pd/C in toluene or benzene, fine gas bubbles appear immediately. The sodium borohydride reacts with the acetic acid, giving, apart from sodium acetate (8), hydrogen and borane. Borane (9), or its formed dimer, diborane (10), would then hydrolyse with the water introduced with the acetic acid and solvents to form boric acid (11) and further hydrogen (Scheme 3). The hydrogen thus produced in situ provides the reagent in the Pd/C catalyzed hydrogenation reaction of the alkenes. The life-time of the borane (9)/diborane (10) produced in the reaction has not been ascertained and so great care must be taken, as borane (9)/diborane (10) are highly toxic, and a complete hydrolysis of the borane with completion of the hydrogenation of the alkenes has not been established.

With NaBH₄, CH₃CO₂H, Pd/C in toluene or benzene, alkenes 12-24, carrying O-benzyl ether functions and/or O-benzyl ester groups could be hydrogenated effectively without loss of the O-benzyl function. Multiple double bonds in a substrate are completely hydrogenated under the conditions as can be seen in the transformation of 22 to 23. Ketones are not reduced with NaBH₄, CH₃CO₂H, (cat.) Pd/C, evident in the conversions of 20/22 to 21/23. Upon careful handling, even a carbaldehyde-function can be retained in the reaction as can be seen in the transformation of 2-benzyloxycinnamaldehyde (24) to 2-benzyloxyphenylpropionaldehyde (25) with only relatively small amounts of 3-(2-benzyloxyphenyl)propanol (26) evident as by-product (Figure 1).

It is known that also ammonia, ammonium acetate and pyridine suppress reductive O-debenzylation with hydrogen in the presence of Pd/C, while the hydrogenation of alkenes proceeds under the conditions [9] . Also, amines have been noted to suppress the reductive cleavage of benzyl ethers [26] -[28] . Momentarily, the mechanistic reasoning behind the suppression of the O-debenzylation in our case is not clear. The accepted mechanism for the Pd(0) hydrogenative O-debenzylation is shown in Scheme 4. It must be noted that the reaction is taken place under heterogeneous conditions, while the mechanism does not take this into account. It is believed that the reductive step D to E is significantly important to determine the character of the “Pd(0)” species and may depend on the reactive system.

Also, N-benzyl cinnamides 27, 29, 31 and 33 were subjected to hydrogenation with NaBH₄, CH₃CO₂H in the presence of cat. Pd/C to afford the corresponding N-benzyl phenylpropionamides 28, 30, 32 and 34 (Scheme 5). Due to the poor solubility of 31 and 33 in toluene or benzene, their hydrogenation was carried out in a mixture of toluene and THF (1/1 v/v). No N-debenzylation was observed in the reactions. Overall, the stability of the benzyl protective group (Bzl) was found to be -NHBzl; -CH₂OCH₂Ph > PhOCH₂Ph > -CO₂CH₂Ph, under the reaction conditions used. This could be seen when N-benzyl 4-methoxy-3-benzyloxycinnamide 33 was subjected to prolonged reaction with NaBH₄, CH₃CO₂H, Pd/C in a solvent mixture of toluene and THF (1:1 v/v), where the O-benzyl function was reductively cleaved as well to give phenol 35 (Scheme 6).

Scheme 2. O-Debenzylation of 3 does not proceed under the conditions.

Scheme 3. Reaction sequences of NaBH₄ (7) in presence of acetic acid (6) and water.

Figure 1

Reduction of alkenes carrying O-benzyl esterand/or O-benzyl ether functions.

Finally, the use hydrogen in presence of Pd/C is an often used method to convert nitroarenes to anilines [29] . Other hydrogen sources such as formic acid and decaborane with Pd/C have been used in the transformation [30] [31] . It was found that nitroarenes are reduced to anilines also with the system NaBH₄ and CH₃CO₂H in the presence of cat. Pd/C. Here, benzyl 4-nitrobenzoate (36) could be converted cleanly to benzyl 4-aminobenzoate (37). Furthermore, benzyl 3-nitrobenzyl ether (38) could be transformed to 3-aminobenzyl benzyl ether (39) (Scheme 7). However, in the case of both benzyl 2-nitrobenzoate (40) and benzyl 2-nitrobenzyl ether (43), the benzyl group was removed reductively to give mixtures of anthranilic acid (42) and benzyl 2-aminobenzoate (41) and of 2-aminobenzyl benzyl ether (44) and 2-aminophenol (45), respectively (Scheme 8). Here, close proximity of the nitro group to the benzyl function leads to partial reductive cleavage of the latter. While the reduction

Scheme 4. Accepted mechanism for Pd(0) catalyzed hydrogenative O-debenzylation.

Scheme 5. Hydrogenation of N-benzyl cinnamides to N-benzyl phenylpropionamides.

Scheme 6. Concomittant O-debenzylation and alkene hydrogenation of 33 with NaBH₄, acetic acid and Pd/C as catalyst.

Scheme 7. Reductive transformation of nitroarenes to anilines with NaBH₄, acetic acid and Pd/C as catalyst.

Scheme 8. Reductive transformation of nitroarenes with benzyl functions in close proximity to the nitro group.

of the nitro group can pass through a number of intermediates and can be mechanistically complex, it is believed that a reactive intermediate along the pathway from nitro- to amino-function leads to the reductive cleavage of the benzyl ether in 44 and benzyl ester in 41.

4. Conclusion

With NaBH₄, AcOH in the presence of catalytic amounts of Pd/C, a simple reactive system was utilized to hydrogenate alkenes in the presence of O-benzyl ether and benzyl ester protective groups, which are not affected by the reaction. It was found that an aromatic nitro function is reduced to amino group by NaBH₄, AcOH, cat. Pd/C. Here a benzyl ether or a benzyl ester function can then be retained, when in the substrate the nitro group and the benzyl function are positioned adequately far apart.

References

1. Russo, A.T., Amezcua, K.L., Huynh, V.A., Rousslang, Z.M. and Cordes, D.B. (2011) A Simple Borohydride-Based Method for Selective 1,4-Conjugate Reduction of α,β-Unsaturated Carbonyl Compounds. Tetrahedron Letters, 52, 6823-6826. http://dx.doi.org/10.1016/j.tetlet.2011.10.056

2. Tran, A.T., Huynh, V.A., Friz, E.M., Whitney, S.K. and Cordes, D.B. (2009) A General Method for the Rapid Reduction of Alkenes and Alkynes Using Sodium Borohydride, Acetic Acid, and Palladium. Tetrahedron Letters, 50, 1817-1819. http://dx.doi.org/10.1016/j.tetlet.2009.02.014

3. Wuts, P.G.M. and Greene, T.W. (2007) Greene’s Protective Groups in Organic Synthesis. 4th Edition, John Wiley & Sons, Hobo-ken.

4. Rylander, P.N. (1985) Hydrogenation Methods. Academic Press, New York, 157-163.

5. Miyazaki, Y., Hagio, H. and Kobayashi, S. (2006) Practical Access to the Polymer Incarcerated Platinum (PI Pt) Catalyst and Its Application to Hydrogenation. Organic Biomolecular Chemistry, 4, 2529-2531. http://dx.doi.org/10.1039/b605288f

6. Wu, G., Huang, M., Richards, M., Poirier, M., Wen, X. and Draper, R.W. (2003) Novel ZnX2-Modulated Pd/C and Pt/C Catalysts for Chemoselective Hydrogenation and Hydrogenolysis of Halogen-Substituted Nitroarenes, Alkenes, Benzyl Ethers, and Aromatic Ketones. Synthesis, No. 11, 1657-1660. http://dx.doi.org/10.1055/s-2003-40878

7. Dovell, F.S. and Greenfield, H. (1965) Platinum Metal Sulfides as Heterogeneous Hydrogenation Catalysts. Journal of the American Chemical Society, 87, 2767-2768. http://dx.doi.org/10.1021/ja01090a050

8. (a) Monguchi, Y., Marumoto, T., Ichikawa, T., Miyake, Y., Nagae, Y., Yoshida, M., Oumi, Y. Sawama, Y. and Sajiki, H. (2015) Unique Chemoselective Hydrogenation Using a Palladium Catalyst Immobilized on Ceramic. ChemCatChem, 7, 2155-2160. http://dx.doi.org/10.1002/cctc.201500193; (b) Esaki, H., Hattori, T., Tsubone, A., Mibayashi, S., Sakata, T., Sawama, Y. Monguchi, Y., Yasuda, H., Nosaka, K. and Sajiki, H. (2013) Chemoselective Hydrogenation Catalyzed by Pd on Spherical Carbon. ChemCatChem, 5, 3629-3635. http://dx.doi.org/10.1002/cctc.201300639; (c) Takahashi, T., Yoshimura, M., Suzuka, H., Maegawa, T., Sawama, Y., Monguchi, Y. and Sajiki, H. (2012) Chemoselective Hydrogenation Using Molecular Sieves-Supported Pd Catalysts: Pd/MS3A and Pd/MS5A. Tetrahedron, 68, 8293-8299. http://dx.doi.org/10.1016/j.tet.2012.07.044; (d) Hattori, T., Tsubone, A., Sawama, Y. Monguchi, Y. and Sajiki, H. (2014) Systematic Evaluation of the Palladium-Catalyzed Hydrogenation under Flow Conditions. Tetrahedron, 70, 4790-4798. http://dx.doi.org/10.1016/j.tet.2014.05.038

9. (a) Sajiki, H. (1995) Selective Inhibition of Benzyl Ether Hydrogenolysis with Pd/C Due to the Presence of Ammonia, Pyridine or Ammonium Acetate. Tetrahedron Letters, 36, 3465-3468. http://dx.doi.org/ 10.1016/0040-4039(95)00527-J; (b) Sajiki, H., Kuno, H. and Hirota, K. (1997) Chemoselective Inhibition of the Hydrogenolysis of the MPM Protective Group for Phenolic Hydroxy Functions Using a Pd/C-Pyridine Catalyst. Tetrahedron Letters, 38, 399-402. http://dx.doi.org/10. 1016/S0040-4039(96)02309-X; (c) Saijiki, H., Kuno, H. and Hirota, K. (1998) Suppression Effect of the Pd/C-Catalyzed Hydrogenolysis of a Phenolic Benzyl Protective Group by the Addition of Nitrogen Containing Bases. Tetrahedron Letters, 39, 7127-7130. http://dx. doi.org/10.1016/S0040-4039(98)01514-7; (d) Sajiki, H. and Hirota, K. (1998) The Formation of a Novel Pd/C Catalyzed Hydrogenation Using a Catalyst Posion: Chemoselective Inhibition of the Hydrogenolysis for O-Benzyl Protective Group by the Addition of a Nitrogen-Containing Base. Tetrahedron, 54, 13981-13996. http://dx.doi.org/10.1016/S0040-4020(98)00882-5; (e) Sajiki, H. and Hirota, K. (2003) Palladium-Catalyzed Chemoselective Hydrogenation in the Presence of a Phenolic MPM Protective Group Using Pyridine as a Catalyst Poison. Chemical and Pharmaceutical Bulletin, 51, 320-324; (e) Sajiki, H., Hattori, K. and Hirota, K. (1998) The Formation of a Novel Pd/C-Ethylenediamine Complex Catalyst: Chemoselective Hydrogenation without Deprotection of the O-Benzyl and ZV-Cbz Groups. The Journal of Organic Chemistry, 63, 7990-7992. http://dx.doi.org/10.1021/jo9814694

10. Sajiki, H. and Monguchi, Y. (2011) Development of Palladium Catalysts for Chemoselective Hydrogenation. In: Pharmaceutical Process Chemistry, Wiley-VCH Verlag, Weinheim, Chpt. 4, 77-79.

11. (a) Mori, A., Miyakawa, Y., Ohashi, E., Haga, T., Maegawa, T. and Sajiki, H. (2006) Pd/C-Catalyzed Chemoselective Hydrogenation in the Presence of Diphenylsulfide. Organic Letters, 8, 3279-3281. http://dx.doi.org/10.1021/ol061147j(b) Mori, A., Mizusaki, T., Miyakawa, Y., Ohashi, E., Haga, T., Maegawa, T., Monguchi, Y. and Sajiki, H. (2006) Chemoselective Hydrogenation Method Catalyzed by Pd/C Using Diphenylsulfide as a Reasonable Catalyst Poison. Tetrahedron, 62, 11925-11932. http://dx.doi.org/10.1016/j.tet.2006.09.094

12. Al Azani, M., Al Sulaibi, M., Al Soom, N., Al Jasem, Y., Bugenhagen, B., Al Hindawi, B. and Thiemann, T. (In Press) The Use of BrCCl3-PPh3 in Appel-Type Transformations to Esters, O-Acyloximes, Amides, and Acid Anhydrides. Submitted to Comptes Rendus Chimie.

13. Rosales, A., Rodríguez-García, I., López-Sánchez, C. and álvarez-Corral, M. (2011) Solvent Influence in the Rh-Catalyzed Intramolecular 1,6 C-H Insertions: A General Approach to the Chromane and Flavanone Skeletons. Tetrahedron, 67, 3071-3075. http://dx.doi.org/10.1016/j.tet.2011.03.004

14. Shiina, I. and Kawakita, Y.-I. (2004) The Effective Use of Substituted Benzoic Anhydrides for the Synthesis of Carboxamides. Tetrahedron, 60, 4729-4733. http://dx.doi.org/10.1016/j.tet.2004.03.066

15. Eliel, E.L. and Anderson, R.P. (1952) Benzyl Esters from Methyl Esters and Benzyldimethylamine. Journal of the American Chemical Society, 74, 547-549. http://dx.doi.org/10.1021/ja01122a081

16. Weast, R.C., Ed. (1972) CRC Handbook of Chemistry and Physics. 53rd Edition, CRC Press, Cleveland.

17. Pearson, A.J. and Lee, K. (1994) A Formal Total Synthesis of the ACE Inhibitor K-13. An Application of Arene- Ruthenium Chemistry to Complex Chemical Synthesis. The Journal of Organic Chemistry, 59, 2304-2313.http://dx.doi.org/10.1021/jo00088a009

18. Arnsberry, K.L. and Borchert, R.T. (1990) The Lactonization of 2’-Hydroxycinnamic Acid Amides, a Potential Prodrug for Amines. The Journal of Organic Chemistry, 55, 5867-5877. http://dx.doi.org/10.1021/jo00310a019

19. Kurian, G.A., Kumar, R., Venkatesh, V., Swesh, S. and Paddikkala, J. (2008) In Vivo and in Vitro Evaluation of Free Radical Scavenging Potential of Methanol Abstract of Desmodium gangeticum Root: A Possible Explanation through GC Mass Analysis. Pharmacognosy Magazine, 4, 162-171.

20. Das, S.K. and Panda, G. (2009) Enantioselective Synthesis of Functionalized 1-Benzoxepins by Phenoxide Ion Mediated 7-endo-tet Carbocyclization of Cyclic Sulfates. European Journal of Organic Chemistry, 2009, 204-207.http://dx.doi.org/10.1002/ejoc.200800661

21. Lee, J. and Lee, L. (1999) A Facile and Practical Synthesis of Capsazepine, a Vallinoid Receptor Antagonist. Synthetic Communications, 29, 4127-4140. http://dx.doi.org/10.1080/00397919908085886

22. Mori, A., Mizusaki, T., Kawase, M., Maegawa, T., Monguchi, Y., Takao, S., Takagi, Y. and Sajiki, H. (2008) Novel Palladium-on-Carbon/Diphenyl Sulfide Complex for Chemoselective Hydrogenation: Preparation, Characterization and Application. Advanced Synthesis & Catalysis, 350, 406-410. http://dx.doi.org/10.1002/adsc.200700571

23. Chen, H., Bashiardes, G., Mailliet, P., Commercon, A., Sounigo, F., Boiziau, J., Parker, F., Tocques, B., Roques, B.P. and Gorbay, C. (1996) Synthesis and Biological Evaluation of a Series of Hydroxybenzylphenylamine Derivatives as Inhibitors of EGF Receptor-Associated Tyrosine Kinase Activity. Anti-Cancer Drug Design, 11, 49-71.

24. Oae, S., Iida, K., Shinhama, T. and Takata, T. (1981) The Pschorr-Cyclization of Aromatic Amines with T-Butyl Thionitrate in Non-Aqueous Media. The Bulletin of the Chemical Society of Japan, 54, 2374-2378.http://dx.doi.org/10.1246/bcsj.54.2374

25. Rousslang, Z.M., Russo, A.T. and Cordes, D.B. (2011) Selec-tive Reductions Using Sodium Borohydride and Palladium. Proceedings of the 241st ACS National Meeting, Anaheim, 27-31 March 2011, CHED-1068.

26. Czech, B.P. and Bartsch, R.A. (1984) Effect of Amines on O-Benzyl Group Hydrogenolysis. The Journal of Organic Chemistry, 49, 4076-4078. http://dx.doi.org/10.1021/jo00195a045

27. Pennings, M.L.M. and Reinhoudt, D.N. (1983) Chemistry of Four-Membered Nitrones. 5. Synthesis and Oxidation of 1-Hydroxyazetidines. The Journal of Organic Chemistry, 48, 4043-4048. http://dx.doi.org/10.1021/jo00170a034

28. Fleet, G.W.J. and Smith, P.W. (1985) Enantioselective Syntheses of Deoxymannojirimycin, Fagomine, and 2R,5R- Dihydroxymethyl-3R,4R-Dihydroxypyrrolidine from D-Glucose. Tetrahedron Letters, 26, 1469-1472.http://dx.doi.org/10.1016/S0040-4039(00)99073-7

29. Vanier, G.S. (2007) Simple and Efficient Microwave-Assisted Hydrogenation Reactions at Moderate Temperature and Pressure. Synlett, 2007, 131-135. http://dx.doi.org/10.1055/s-2006-958428

30. Berthold, H., Schotten, T. and Honig, H. (2002) Transfer Hydrogenation in Ionic Liquids under Microwave Irradiation. Synthesis, 1607-1610.

31. Bae, J.W., Cho, Y.J., Lee, S.H., Yoon, C.O.M. and Yoon, C.M. (2000) One-Pot Synthesis of N-Alkylaminobenzenes from Nitroaromatics: Reduction Followed by Reductive Amination Using B10H14. Chemical Communications, 1857- 1858.