Hydrogenation of (N,N-disubstituted aminomethyl)nitrobenzenes to (N,N-disubstituted aminomethyl)anilines catalyzed by palladium–nickel bimetallic nanoparticles

Abstract

Since palladium-catalysts have strong abilities for both hydrogenation of nitro-group and hydrogenolysis of benzylamine, they have a much lower chemoselectivity for the hydrogenation of (N,N-disubstituted aminomethyl)nitrobenzenes. In this article, component stable Pd–Ni bimetallic nanoparticles were prepared by simply heating RANEY®-Ni and Na₂PdCl₄ together in water. They demonstrated novel synergistic effects when they were used as a bimetallic catalyst, by which a highly efficient and chemoselective hydrogenation of (N,N-disubstituted aminomethyl)nitrobenzenes to (N,N-disubstituted aminomethyl)anilines was achieved.

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Introduction

The catalytic hydrogenation of nitrobenzenes is the most preferred method for the synthesis of anilines due to its high efficiency and easy procedures. Pd-catalysts are often employed for this purpose in both academic and industry laboratories because they have lower costs than Pt-catalysts and higher efficiency than Ni-catalysts.¹ Since Pd-catalysts also have a strong ability for the catalytic hydrogenolysis of carbon-heteroatom bonds, they have a much lower chemoselectivity for the hydrogenation of (N,N-disubstituted aminomethyl)nitrobenzenes 1.^2,3

In 1999, the first small-molecule, non-peptide CCR5 antagonist TAK-779 was reported to have highly potent and selective anti-HIV-1 activity.⁴ As shown in Fig. 1, its molecule contains a structural unit of (N,N-disubstituted aminomethyl)aniline 2. In recent years, the syntheses of structural units 2 have been gaining importance because they have been recognized as key pharmacophores and synthetic intermediates in drug discovery.^5–7 The most convenient synthesis of 2 can be achieved by chemoselective reduction of 1. Unfortunately, the most reliable method for this conversion was the dissolving metal reduction⁵ rather than the catalytic hydrogenation.⁷

Fig. 1 The structure of TAK-779.

As shown in Scheme 1, a detailed study was reported by Hashimoto et al.^5f for the synthesis of N-[(4-aminophenyl)-methyl]tetrahydro-N-methyl-2H-pyran-4-amine (2j) from N-[(4-nitrophenyl)methyl]tetrahydro-N-methyl-2H-pyran-4-amine (1j). Under the catalytic hydrogenation conditions, the desired product 2j was obtained in trace yield over Pd–C or RANEY®-Ni catalyst (entries 1 and 2). Finally, the combination of SnCl₂/aq. HCl was employed as a reducing reagent for this conversion. The experiment in entry 1 was carefully repeated in our laboratory and the benzyl–nitrogen bond in 1j was hydrogenolyzed completely to give the corresponding 3j and 4j.

Scheme 1 A detailed study for the reduction of 1j to 2j.

Herein, we would like to report a convenient preparation of Pd–Ni bimetallic nanoparticles. When they were used as a bimetallic catalyst, a general method was developed for highly efficient and chemoselective hydrogenation of 1 to 2.

Results and discussion

Traditionally, the chemoselectivity of Pd-catalysts are modulated by using the catalyst poisons. For example, PbO/PbAc₂ or quinoline is employed for such purpose in Lindlar catalysts.⁸ Rosenmund reduction can be well modulated by in situ adding thioquinanthrene or thiourea into the hydrogenation processes.⁹ Pd–C(en) is a versatile catalyst for chemoselective hydrogenations, in which ethylenediamine is used as the poison.¹⁰ However, these reported catalytic systems are not all suitable for the chemoselective hydrogenation of 1 to 2. As shown in Scheme 2, this conversion was first achieved in our previous work,¹¹ but the concentrated aqueous HCl was used as the poison for the Pd–C catalyst.

Scheme 2 A reported chemoselective hydrogenation of 1 to 2.

Recently, the catalytic applications of bimetallic nanoparticles have been developing quickly.¹² These bimetallic catalysts often showed novel catalytic activity and chemoselectivity based on their unique electronic effect (or ligand effect) and geometric effect (or strain effect). Many methods have been reported for the preparation of bimetallic catalysts in literature. However, our attention was attracted by several early reported references,¹³ in which the bimetallic catalysts were prepared by simply mixing a RANEY®-metal [M = Ni(0), Cu(0)] with a noble metal precursor [M¹ = Pt(IV), Ru(III), Au(III), Pd(II)] together. Since the RANEY®-metal is a porous solid and has low redox potential, the noble metal precursor is reduced to a zero-valent metal [M¹(0)] to disperse on the surface of the RANEY®-metal. In these preparations, RANEY®-metal plays three roles as a reducing reagent, a support and one component of the bimetallic catalyst. Thus, we were inspired to prepare a Pd–Ni bimetallic catalyst by the similar method. As shown in Scheme 3, when the mixture of RANEY®-Ni (99 wt%) and Na₂PdCl₄ (containing 1 wt% of Pd) in water was heated at 120 °C for 6 h in an autoclave, a component stable Pd–Ni bimetallic catalyst was obtained as black powders.

Scheme 3 Preparation of the Pd–Ni bimetallic catalyst.

ICP analyses showed that Pd/Ni ratio in this bimetallic catalyst was about 1 : 99 ± 3 (by wt%). TEM images showed that the bimetallic catalyst was nanosized particles (Fig. 2). Since it contains only 1 wt% of Pd(0), its XRD patterns had no significant differences with RANEY®-Ni (Fig. 3) and the peak of only Pd(111) was observed.

Fig. 2 TME images of Pd–Ni bimetallic nanoparticles.

Fig. 3 XRD patterns of RANEY®-Ni (a) and Pd–Ni bimetallic nanoparticles (b).

Then, the catalytic property of this Pd–Ni bimetallic catalyst was tested by using the hydrogenation of 4-(N,N-dimethyl-aminomethyl)nitrobenzene (1a) into 4-(N,N-dimethyl-aminomethyl)aniline (2a) as a model reaction. As shown in entry 1 in Table 1, 2a was obtained in 90% yield and 93% chemoselectivity over Pd–C catalyst. Low conversion of 1a was observed over RANEY®-Ni and a mixture was obtained caused by the hydrogenation intermediates (entry 2).¹⁴ As was expected, 1a was hydrogenated into 2a in quantitative yield and chemoselectivity over Pd–Ni bimetallic catalyst (entry 3). Since this experiment employed the same amounts of palladium (net weight) as that in entry 1 and nickel (net weight) as that in entry 2, the Pd–Ni bimetallic catalyst clearly demonstrated its advantages and synergistic effects. Use of 30 wt% of the Pd–Ni bimetallic catalyst gave the same excellent results (entry 4), while use of 20 wt% of the Pd–Ni bimetallic catalyst resulted in low conversion of 1a (entry 5). However, this problem can be solved easily by slightly increasing the hydrogen pressure (entries 6 and 7).

Table 1 Hydrogenations of 1a catalyzed by three catalysts^a

Entry	Catalyst (wt%)	Net weight of metal (mg)	Time (min)	Yield of 2a^b (%)	Selectivity (%)
a A mixture of 1a (180 mg, 1 mmol) and a catalyst in MeOH (10 mL) was stirred under H2 at room temperature and atmospheric pressure (on an atmospheric pressure hydrogenation apparatus). b Separated yield was obtained. c 85% conversion of 1a was obtained. d The hydrogenation proceeded under 80 psi.
1	5% Pd–C (10)	Pd (0.9)	120	90	95
2	RANEY®-Ni (50)	Ni (90)	150	85^c	Mixture
3	1% Pd–Ni (50)	Pd (0.9), Ni (89.1)	50	99	100
4	1% Pd–Ni (30)	Pd (0.54), Ni (53.5)	90	99	100
5	1% Pd–Ni (20)	Pd (0.36), Ni (25.6)	140	85	100
6	1% Pd–Ni (10)	Pd (0.18), Ni (17.8)	180	55	100
7^d	1% Pd–Ni (5)	Pd (0.09), Ni (8.91)	210	93	100

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Unlike the commercial RANEY®-Ni catalyst, Pd–Ni bimetallic catalyst (in both wet and dry forms) is stable to air and no auto-ignition has occurred so far. However, its catalytic activity was influenced significantly by the reaction solvents. As shown in Table 2, all tested lower alcohols were excellent solvents for this catalytic hydrogenation (entries 1–4). But non-alcohol solvents, both polar solvents (entries 5–6) and non-polar solvents (entries 7–9), were not suitable for this purpose. This phenomenon may be partly caused by the fact that the Pd–Ni bimetallic nanoparticles could be fully dispersed in the lower alcohols, while it formed agglomerated particles in the non-alcohol solvents.

Table 2 Effect of the solvents on the hydrogenations of 1a^a

Entry	Solvent	Time^b (min)	Yield of 2a^c (%)
a A mixture of 1a (180 mg, 1 mmol) and Pd–Ni bimetallic catalyst in the tested solvent (10 mL) was stirred under H2 at room temperature and atmospheric pressure (on an atmospheric pressure hydrogenation apparatus). b The time was when the absorption of hydrogen ceased. c Separated yield was obtained.
1	MeOH	90	99
2	EtOH	110	96
3	i-PrOH	210	94
4	n-BuOH	330	93
5	THF	600	81
6	EtOAc	720	75
7	DCM	480	47
8	Cyclohexane	300	5
9	Toluene	300	4

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Finally, the standard procedure was assigned as shown in Scheme 4 and the reaction scope was tested. There was no difference caused by the substituted position of a nitro-group on the benzene ring (2a–2c). But, the chemoselectivity was influenced significantly by the size of the group substituted on the benzylamine, and decreased sharply by the increase of the size (2d–2h, 2n–2p). To improve the chemoselectivity of 2h, the hydrogenation of 1h at 0 °C was tested. Unfortunately, the chemoselectivity of 2h increased 9% while the yield of 2h decreased 7% because the hydrogenation of 1h automatically stopped within 16 h. We interestingly observed that the excellent chemoselectivity could be achieved as long as one group is a methyl group (2i–2j, 2n). The cyclic substituents seemed to be “small-sized groups” and gave both quantitative yields and chemoselectivity (2k–2m). For easy purification of the analytical samples, three products were converted into their amides derivatives (2o–2q). To our surprise, 2r was prepared smoothly in the presence of 40 wt% of Pd–Ni bimetallic catalysts.

Scheme 4 The scope of the chemoselective hydrogenation.

Since the Pd–Ni bimetallic catalyst has magnetic property, it can be separated and recovered conveniently in work-up process with a magnetic stirring bar, which could greatly facilitate the recycling of the catalyst. As shown in Table 3, a recycling study shows that the catalytic activity of the Pd–Ni bimetallic catalyst decreased steadily in the first three recycles (entries 1–3). But, the yield and chemoselectivity of the product 2a were not influenced by prolonging the reaction time. Unfortunately, its catalytic activity dropped sharply in the fourth recycle (entry 4), presumably because of the loss of the “nonmagnetic palladium metal” during the separation and recovery of the catalyst. In fact, the proportion of palladium metal in the Pd–Ni bimetallic catalyst in the fourth recycle was 18% lower than that in the fresh catalyst.

Table 3 Recycling study of the Pd–Ni bimetallic catalyst^a

Recycle times	Time^b (min)	Yield of 2a^c(%)
a A mixture of 1a (180 mg, 1 mmol) and Pd–Ni bimetallic catalyst in MeOH (10 mL) was stirred under H2 at room temperature and atmospheric pressure (on an atmospheric pressure hydrogenation apparatus). b The time was when the absorption of hydrogen ceased. c Separated yield was obtained. d Only 1a (25%) and 2a (75%) were detected in the reaction mixture by ^1H NMR.
1	90	99
2	210	97
3	450	94
4	900	75^d

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Conclusions

A highly efficient and chemoselective hydrogenation of (N,N-disubstituted aminomethyl)nitrobenzenes to (N,N-disubstituted aminomethyl)anilines was developed. Its success was due to the novel catalytic activity of the Pd–Ni bimetallic nanoparticles. In literature, the reported bimetallic catalyst usually demonstrated higher catalytic activity than both componential metals by their synergistic effects. However, our Pd–Ni bimetallic catalyst demonstrated that the catalytic activity of RANEY®-Ni was enhanced and the chemoselectivity of Pd was enhanced. This hydrogenation may be widely used since the Pd–Ni bimetallic catalyst can be prepared conveniently and the products are very useful in the drug discovery.

Experimental section

General information

All melting points were determined on a Yanaco melting point apparatus and were uncorrected. IR spectra were recorded as KBr pellets on a Nicolet FT-IR 5DX spectrometer. All spectra of ¹H NMR and ¹³C NMR were recorded on a JEOL JNM-ECA 300 or 400 spectrometers in CDCl₃ and TMS was used as an internal reference. HRMS were obtained on a Bruker micrOTOF-Q II spectrometer.

Preparation of 1% Pd–Ni bimetallic catalyst. The suspension of RANEY®-Ni (1.0 g) and Na₂PdCl₄ (80.66 mg, containing 10 mg of palladium) in H₂O (8 mL) in a stainless Teflon-lined 10 mL-capacity autoclave was heated at 120 °C for 6 h. After the reaction system was cooled down to room temperature, the black powders were collected and washed by water in three times. It was stored in distillated H₂O before uses.

Typical procedure for hydrogenation of 4-(N,N-dimethyl-aminomethyl)nitrobenzene (1a) into 4-(N,N-dimethyl-aminomethyl)aniline (2a). A mixture of 1a (180 mg, 1 mmol) and 1% Pd–Ni bimetallic catalyst (54 mg, 30 wt%) in MeOH (10 mL) was stirred under H₂ at room temperature and atmospheric pressure (on an atmospheric pressure hydrogenation apparatus) until the absorption of hydrogen ceased (90 min). After the catalyst was removed off by a magnetic stirring bar, the solution was evaporated in a vaporator to give the product 2a as yellowish oil (148 mg, 99%), which is pure enough for ¹H and ¹³C NMR determinations.^15a1H NMR (CDCl₃, 400 MHz) δ 7.07 (d, 2H, J = 8.28 Hz), 6.64 (d, 2H, J = 7.76 Hz), 3.59 (s, 2H), 3.32 (s, 2H), 2.21 (s, 6H); ¹³C NMR (CDCl₃, 100 MHz) δ 145.4, 130.3 (2C), 128.5, 114.9 (2C), 63.8, 45.0 (2C).

The similar procedure was used for the chemoselective hydrogenation of 1b–1r to 2b–2r. In some cases, the flash chromatography was required for the purification of the products.

3-(N,N-Dimethyl-aminomethyl)aniline (2b)^15b. Yellowish oil, 98% yield. ¹H NMR (CDCl₃, 400 MHz) δ 7.11–7.09 (m, 1H), 6.69–6.57 (m, 3H), 3.62 (s, 2H), 3.33 (s, 2H), 2.23 (s, 6H); ¹³C NMR (CDCl₃, 100 MHz) δ 146.4, 140.2, 129.1, 119.4, 115.6, 113.9, 64.4, 45.4 (2C).
2-(N,N-Dimethyl-aminomethyl)aniline (2c)^15c. Yellowish oil, 97% yield. ¹H NMR (CDCl₃, 400 MHz) δ 7.08–6.96 (m, 2H), 6.66–6.62 (m, 2H), 3.40 (s, 2H), 2.19 (s, 6H); ¹³C NMR (CDCl₃, 100 MHz) δ 147.0, 130.3, 128.2, 123.3, 117.5, 115.4, 63.4, 44.9 (2C).
4-(N,N-Diethyl-aminomethyl)aniline (2d). Yellowish oil, 98% yield. IR (KBr) v 3449, 2969, 2801, 1620, 1616, 1281 cm⁻¹; ¹H NMR (CDCl₃, 400 MHz) δ 7.10 (d, 2H, J = 8.24 Hz), 6.63 (d, 2H, J = 8.72 Hz), 3.59 (s, 2H), 3.46 (s, 2H), 2.50 (q, 4H, J = 7.36 Hz), 1.03 (t, 6H, J = 7.32 Hz); ¹³C NMR (CDCl₃, 100 MHz) δ 145.0, 130.1 (2C), 129.5, 114.9 (2C), 56.8, 46.4 (2C), 11.6 (2C); HRMS (ESI-TOF) (m/z): calcd for C₁₁H₁₈N₂, [M + H]⁺ 179.1543; found 179.1545.
4-(N,N-Dipropyl-aminomethyl)aniline (2e). Yellowish oil, 98% yield. IR (KBr) v 3349, 2798, 1621, 1516, 1459, 1274, 1173 cm⁻¹; ¹H NMR (CDCl₃, 400 MHz) δ 7.10 (d, 2H, J = 11.0 Hz), 6.64 (d, 2H, J = 11.4 Hz), 3.55 (s, 2H), 3.43 (s, 2H), 2.34 (t, 4H, J = 10.08 Hz), 1.49–1.42 (m, 4H), 0.84 (t, 6H, J = 10.08 Hz); ¹³C NMR (CDCl₃, 100 MHz) δ 144.8, 130.0 (2C), 129.8, 114.8 (2C), 57.9, 55.6 (2C), 20.1 (2C), 11.9 (2C); HRMS (ESI-TOF) (m/z): calcd for C₁₃H₂₂N₂, [M + H]⁺ 207.1856; found 207.1857.
4-(N,N-Diisopyl-aminomethyl)aniline (2f). Yellowish oil, 90% yield. IR (KBr) v 3353.12, 2964, 2811, 1620, 1514, 1462, 1272 cm⁻¹; ¹H NMR (CDCl₃, 300 MHz) δ 7.15 (d, 2H, J = 8.25 Hz), 6.63 (d, 2H, J = 8.58 Hz), 3.52 (s, 4H), 3.02–2.97 (m, 2H), 1.01 (S, 6H), 0.99 (S, 6H); ¹³C NMR (CDCl₃, 75 MHz) δ 144.5, 133.0, 128.9 (2C), 114.9 (2C), 48.1, 47.3 (2C), 20.7 (4C); HRMS (ESI-TOF) (m/z): calcd for C₁₃H₂₂N₂, [M + H]⁺ 207.1856; found 207.1860.
4-(N,N-Dibutyl-aminomethyl)aniline (2g). Yellowish oil, 89% yield. IR (KBr) v 3355, 2956, 2796, 1621, 1515, 1274 cm⁻¹; ¹H NMR (CDCl₃, 400 MHz) δ 7.09 (d, 2H, J = 8.28 Hz), 6.63 (d, 2H, J = 8.28 Hz), 3.58 (s, 2H), 3.44 (s, 2H), 2.37 (t, 4H, J = 7.32 Hz), 1.43–1.41 (m, 4H), 1.30–1.26 (m, 4H), 0.87 (t, 6H, J = 7.32 Hz); ¹³C NMR (CDCl₃, 75 MHz) δ 144.9, 129.9 (2C), 129.8, 114.9 (2C), 57.9, 53.2 (2C), 29.1 (2C), 20.6 (2C), 14.1 (2C); HRMS (ESI-TOF) (m/z): calcd for C₁₅H₂₆N₂, [M + H]⁺ 235.2169; found 235.2165.
4-(N,N-Dicyclohexyl-aminomethyl)aniline (2h)¹¹. Yellowish oil, 80% yield. ¹H NMR (CDCl₃, 400 MHz) δ 7.14 (d, 2H, J = 11.0 Hz), 6.62 (d, 2H, J = 10.6 Hz), 3.62 (s, 2H), 3.54 (s, 2H), 2.54–2.49 (m, 2H), 1.73–1.15 (m, 20H); ¹³C NMR (CDCl₃, 75 MHz) δ 144.3, 133.5, 128.7 (2C), 114.9 (2C), 57.4 (2C), 49.3, 31.9 (4C), 26.5 (4C), 26.3 (2C).
4-(N-Methyl-N-cyclohexyl-aminomethyl)aniline (2i)^5e. Yellowish oil, 99% yield. ¹H NMR (CDCl₃, 300 MHz) δ 7.09 (d, 2H, J = 8.25 Hz), 6.64 (d, 2H, J = 8.24 Hz), 3.57 (s, 2H), 3.44 (s, 2H), 2.44–2.39 (m, 1H), 2.16 (s, 3H), 1.85–1.16 (m, 10H); ¹³C NMR (CDCl₃, 75 MHz) δ 144.9, 130.0, 129.8 (2C), 114.9 (2C), 62.1, 57.2, 37.4, 28.6 (2C), 26.4, 26.0 (2C).
4-[N-Methyl-N-(tetrahydropyran-4-yl)-aminomethyl]aniline (2j)^5f. Yellowish oil, 98% yield. ¹H NMR (CDCl₃, 400 MHz) δ 7.09 (d, 2H, J = 7.76 Hz), 6.64 (d, 2H, J = 8.24 Hz), 4.00–4.03 (m, 2H), 3.49 (s, 2H), 3.39 (s, 2H), 3.38–3.35 (m, 2H), 2.65–2.63 (m, 1H), 2.20 (s, 3H), 1.75–1.68 (m, 4H); ¹³C NMR (CDCl₃, 75 MHz) δ 145.3, 130.0 (2C), 129.0, 115.0 (2C), 67.6 (2C), 59.3, 57.2, 37.2, 29.1 (2C).
4-(Pyrrolidin-1-yl)methyl aniline (2k). Yellowish oil, 99% yield. IR (KBr) v 3372, 2929, 1623, 1582, 1382, 1288 cm⁻¹; ¹H NMR (CDCl₃, 400 MHz) δ 7.11 (d, 2H, J = 8.24 Hz), 6.64 (d, 2H, J = 8.24 Hz), 3.60 (s, 2H), 3.50 (s, 2H), 2.49–2.46 (m, 4H), 1.78–1.75 (m, 4H); ¹³C NMR (CDCl₃, 100 MHz) δ 145.2, 130.1 (2C), 129.3, 114.9 (2C), 60.1, 53.9 (2C), 23.3 (2C); HRMS (ESI-TOF) (m/z): calcd for C₁₁H₁₆N₂, [M + H]⁺ 177.1386; found 177.1388.
4-(Piperidin-1-yl)methyl aniline (2l)^5d. Yellowish oil, 98% yield. ¹H NMR (CDCl₃, 400 MHz) δ 7.09 (d, 2H, J = 8.28 Hz), 6.63 (d, 2H, J = 8.24 Hz), 3.60 (s, 2H), 3.38 (s, 2H), 2.42–2.30 (m, 4H), 1.61–1.52 (m, 4H), 1.42–1.38 (m, 2H); ¹³C NMR (CDCl₃, 100 MHz) δ 145.2, 130.4 (2C), 128.1, 114.8 (2C), 63.3, 54.2 (2C), 25.9 (2C), 24.4.
4-(Morpholin-1-yl)methyl aniline (2m). Yellowish solid, mp 100–102 °C (lit.^15d mp 100–102 °C), 97% yield. ¹H NMR (CDCl₃, 300 MHz) δ 7.10 (d, 2H, J = 8.24 Hz), 6.64 (d, 2H, J = 8.25 Hz), 3.70–3.67 (m, 4H), 3.62 (s, 2H), 3.37 (s, 2H), 2.42–2.39 (m, 4H); ¹³C NMR (CDCl₃, 75 MHz) δ 145.4, 130.3 (2C), 127.5, 114.9 (2C), 67.0 (2C), 63.0, 53.5 (2C).
4-(N-Methyl-N-phenyl-aminomethyl)aniline (2n)^15e. Yellowish oil, 99% yield. ¹H NMR (CDCl₃, 300 MHz) δ 7.21–7.19 (m, 2H), 6.75–6.58 (m, 7H), 4.38 (s, 2H), 3.55 (s, 2H), 2.93 (s, 3H); ¹³C NMR (CDCl₃, 75 MHz) δ 149.9, 145.1, 129.0 (2C), 128.6, 127.9 (2C), 116.3, 115.2 (2C), 112.4 (2C), 56.0, 38.1.
N-[4-(N-Ethyl-N-phenyl-aminomethyl)phenyl]acetamide (2o). Yellowish oil, 88% yield. IR (KBr) v 3285, 3185, 2967, 1658, 1598, 1505, 1408, 1248 cm⁻¹; ¹H NMR (CDCl₃, 300 MHz) δ 7.42–7.14 (m, 7H), 6.69–6.63 (m, 3H), 4.46 (s, 2H), 3.44 (q, 2H, J = 6.87 Hz), 2.14 (s, 3H), 1.18 (t, 3H, J = 6.87 Hz); ¹³C NMR (CDCl₃, 75 MHz) δ 168.4, 148.3, 136.5, 135.1, 129.1 (2C), 127.0 (2C), 120.2 (2C), 116.0, 112.1 (2C), 53.4, 45.0, 24.3, 12.0; HRMS (ESI-TOF) (m/z): calcd for C₁₇H₂₀N₂O, [M + Na]⁺: 291.1468; found 291.1463.
N-[4-(N-Butyl-N-phenyl-aminomethyl)phenyl]acetamide (2p). Yellowish oil, 85% yield. IR (KBr) v 3286, 2952, 2867, 1659, 1599, 1505, 1408, 1317 cm⁻¹; ¹H NMR (CDCl₃, 400 MHz) δ 7.25–7.13 (m, 7H), 6.67–6.63 (m, 2H), 4.48 (s, 2H), 3.33–3.38 (m, 2H), 2.15 (s, 3H), 1.62–1.60 (m, 2H), 1.35–1.33 (m, 2H), 0.94 (t, 3H, J = 9.64 Hz); ¹³C NMR (CDCl₃, 75 MHz) δ 168.3, 148.5, 136.4, 135.1, 129.1 (2C), 127.0 (2C), 120.2 (2C), 115.9, 112.1 (2C), 54.0, 51.0, 29.2, 24.4, 20.3, 13.9; HRMS (ESI-TOF) (m/z): calcd for C₁₉H₂₄N₂O, [M + Na]⁺ 319.1781; found 319.1779.
N-[2-[N-Methyl-N-(2-chlorophenyl)-aminomethyl]phenyl]acetamide (2q). Yellowish oil, 88% yield. IR (KBr) v 3260, 2854, 2803, 1686, 1516, 1443, 1304 cm⁻¹; ¹H NMR (CDCl₃, 300 MHz) δ 9.82 (s, 1H), 8.22–8.19 (m, 1H), 7.40–7.02 (m, 7H), 4.17 (s, 2H), 2.62 (s, 3H), 2.16 (s, 3H); ¹³C NMR (CDCl₃, 75 MHz) δ 168.6, 148.4, 138.3, 130.5, 130.2, 129.5, 128.6, 127.8, 125.3, 125.2, 123.4, 121.9, 121.6, 58.8, 41.9, 24.7; HRMS (ESI-TOF) (m/z): calcd for C₁₆H₁₇ClN₂O, [M + Na]⁺ 311.0922; found 311.0920.
Tris-(4-aminobenzyl)-amine (2r)^15f. Yellow gum, 98% yield. ¹H NMR (CDCl₃, 300 MHz) δ 7.12 (d, 6H, J = 8.25 Hz), 6.66 (d, 6H, J = 8.25 Hz), 3.66 (s, 6H), 3.60 (s, 6H); ¹³C NMR (CDCl₃, 75 MHz) δ 145.1 (3C), 130.4 (3C), 129.2 (6C), 115.0 (6C), 52.5 (3C).

Acknowledgements

This work was supported by NNSF of China (nos 21221062, 21372142 and 21472107).

Notes and references

1. (a) S. Nishimura, Handbook of heterogeneous catalytic hydrogenation for organic synthesis, John Wiley & Sons, Inc., New York, 2001, ch. 9; (b) P. N. Rylander, Hydrogenation methods, Academic Press, London, 1985, ch. 8.
2. (a) S. Nishimura, Handbook of heterogeneous catalytic hydrogenation for organic synthesis, John Wiley & Sons, Inc., New York, 2001, ch. 13; (b) P. N. Rylander, Hydrogenation methods, Academic Press, London, 1985, ch. 13.
3. In general, the order of ease of hydrogenolysis of benzylamines is tertiary > secondary > primary. N,N-Disubstituted benzylamine smoothly underwent a hydrogenolysis over Pd–C catalyst, while benzylamine and N-monosubstituted benzylamine usually stayed intact. Therefore, only N,N-disubstituted benzylamines were suitable to be used as protective groups, see: T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, Inc., New York, 3rd edn, 1999.
4. M. Baba, O. Nishimura, N. Kanzaki, M. Okamoto, H. Sawada, Y. Iizawa, M. Shiraishi, Y. Aramaki, K. Okonogi, Y. Ogawa, K. Meguro and M. Fujino, Proc. Natl. Acad. Sci. U. S. A, 1999, 96, 5698–5703.
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Footnote

† Electronic supplementary information (ESI) available: ¹H and ¹³C NMR spectra for products 2a–2r. See DOI: 10.1039/c5ra07208e

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