Simple, versatile, and chemoselective reduction of secondary amides and lactams to amines with the Tf₂O–NaBH₄ or Cp₂ZrHCl–NaBH₄ system

Abstract

The reduction of secondary amides to amines is an important transformation for the total synthesis of alkaloids and pharmaceuticals. General and chemoselective direct methods for this transformation are scarce. We report in this paper a simple method for the direct reduction of secondary amides, which uses only two reagents, triflic anhydride for amide activation, and NaBH₄ for reduction. Running under mild conditions (0 °C to r.t.), the reaction works well with several types of secondary amides including aromatic amides, aliphatic amides, and α,β-unsaturated amides. The reaction displays a good functional group tolerance for a series of reducible functional groups. The method is applicable to the direct reduction of C–H lithiation-functionalization products, and C–H activation-functionalization products. Moreover, chemoselective reduction of secondary lactams has been achieved using Cp₂ZrHCl–NaBH₄ combination.

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Introduction

The reduction of amides to amines is an important transformation for the synthesis of bioactive alkaloids and N-containing medicinal agents.¹ Due to the high stability of amides, use of strong reducing agents² such as LiAlH₄,³ diborane,⁴ borane-THF/SMe₂ complex,⁵ and DIBAL-H⁶ is generally required. In addition, sometimes the reduction reaction needs to be run under harsh conditions. As for the reduction of secondary amides, the classical Brown reduction with the borane-THF/SMe₂ complex is incompatible with alkenyl and alkynyl groups, and requires an extra step to dissociate borane–amine adducts.⁷ It is not surprising that the classical methods have low functional group tolerance and may lead to undesired products.^3,8 These factors can account for the fact that stepwise protocols involving the pre-transformation of amides to thioamides^1e–i,l or the pre-transformation of secondary amides to imides⁹ are methods of choice in the synthesis of alkaloids and medicinal agents.¹ To suit the needs of modern organic synthesis and pharmaceutical chemistry, development of chemoselective methods for the direct reduction of amides has attracted considerable attention, and significant progress has been made in recent years.^10,11 However, chemoselective reduction of amides under mild conditions remains a challenging issue,^10a,b,e in particular for secondary amides,¹² which contain both a highly stabilized carbonyl and an active proton. Only limited examples involving chemoselective reduction of secondary amides have been reported.¹²

General and chemoselective methods with a broad functional group tolerance are rare, which include Charette's chemoselective reduction utilizing the Tf₂O/2-F-Py/Et₃SiH/Hantzsch ester hydride (HEH) system,^12b Nagashima's Ru^11e and Pt^10l catalyzed hydrosilylations, Beller's zinc-catalyzed chemoselective reduction,^12c and boronic acid catalyzed selective hydrosilylation,¹²ⁱ Reeves’ Ru-catalyzed hydrosilylation,^12f as well as Luo's low-valent titanium reduction.^12g Moreover, secondary amides serve as powerful directing groups for both directed lithiation-functionalization¹³ and C–H activation-functionalization.¹⁴ Thus, simple methods for direct and chemoselective reduction of secondary amides are still highly demanding.¹⁵

As a continuation of our program on the development of synthetic methodology for the direct transformations of amides,¹⁶ we reported recently the first general method for the direct reductive alkylation of secondary amides¹⁵ⁿ and a Tf₂O-based¹⁷ method for the reduction of amides A to give amines B (Scheme 1).¹⁰ⁿ The latter report also includes secondary amides 1-1 and 1-2. Herein, we report the results of a systematic investigation on the direct and chemoselective reduction of secondary amides to amines.

Scheme 1

Results and discussion

In our previous report,¹⁰ⁿ the optimal conditions defined for the direct reduction of tertiary amides were adapted for the reduction of secondary amides 1-1 and 1-2. Thus in the present investigation, Tf₂O and NaBH₄ were retained for the in situ amide activation and the reduction of the presumed imidoyl triflate intermediates, while other reaction parameters including a solvent (THF, Et₂O, MTBE) and equivalents of sodium borohydride (1.3–2.0 mol equiv.) were re-examined. With Tf₂O/CH₂Cl₂–NaBH₄ (1.3 mol equiv.)/THF combination, the reduction of N-i-propylbenzamide 1a gave amine 2a in 74% yield along with 9% of the recovered starting amide (Table 1, entry 1). Next, the effects of 2-fluoropyridine (2-F-Py) were examined. As can be seen from Table 1, use of 0.5 mol equiv. of 2-F-Py (Table 1, entry 2) resulted in an increase of the yield of amine 2a by 5%. However, the yield based on the recovered starting material remained the same. Surprisingly, use of more equiv. of 2-F-Py led to a drop of yield (Table 1, entries 3–5), which is attributed to the competing reduction reaction of the 2-fluoropyridinium ion at a higher concentration. On balancing the yield and atom economy, the optimal conditions for the amide reduction were defined as: Tf₂O (1.1 mol equiv.)/CH₂Cl₂ (0.25 M)–NaBH₄ (1.3 mol equiv.)/THF.

Table 1 The effects of 2-fluoropyridine on the Tf₂O-activated reduction of secondary amides

Entry	2-F-Py (equiv.)	% Yield of 2a^a
a Isolated yield. b Yield based on the recovered starting amide. c Only trace of the starting amide was observed on TLC.
1	0	74 (83)^b
2	0.5	79 (83)^b
3	1.2	67 (ca. 67)^c
4	1.5	66 (ca. 66)^c
5	2.0	60 (ca. 60)^c

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With the optimal conditions in hand, the scope of the reduction was investigated, and the results are summarized in Table 2. We first examined the effects of substituents on the reduction of aromatic amides. As can be seen from entries 1 to 4 and entries 5 to 9 of Table 2, the reactions worked similarly for benzamide derivatives bearing both electron-donating groups (entries 2, 3 and 6) and electron-withdrawing groups (entries 4, 7–9) at the para-position. Slightly lower yields were obtained from substrates bearing an electron donating group. N-i-Propyl and N-c-hexylbenzamides gave similar results (entries 1, 2 versus 5, 6). In addition to ether (entry 3), halo (entries 4, 7 and 8), and CF₃ (entry 9) groups, the functional group tolerance of the reaction was further examined. The results shown in entries 10–12 indicate that the reaction also tolerates para-substituted ester, cyano and nitro groups. α,β-Unsaturated amide 1m also reacted chemoselectively to produce the corresponding amine 2m in 65% yield (entry 13). Surprisingly, the reaction of m-bromobenzamide 1n gave the corresponding amine 2n in a lower yield of 64% (entry 14). Good yield was obtained with N-isopropyl-1-naphthamide (entry 15, yield: 78%). It is noteworthy that N-isopropyl-3-phenylpropanamide 1p, an aliphatic amide, also reacted smoothly to give amine 2p in 70% yield (entry 16). However, the reduction of the more hindered N-isopropyl-2-phenylbutanamide 1q afforded the corresponding amine 2q in a modest yield of 63% (entry 17). Interestingly, the reduction of (S)-N-(1-phenylethyl)benzamide 1r produced the corresponding amine 2r in 65% yield (entry 18).

Table 2 Tf₂O-activated reduction of secondary amides with NaBH₄

Entry	Substrate (R^1, R^2)	Product: % yield^a
a Isolated yield. b Yield based on the recovered starting amide.
1	1a (Ph, i-Pr)	2a: 74 (83)^b
2	1b (p-MeC6H4, i-Pr)	2b: 67 (74)^b
3	1c (p-MeOC6H4, i-Pr)	2c: 71 (79)^b
4	1d (p-ClC6H4, i-Pr)	2d: 73 (86)^b
5	1e (Ph, c-hex)	2e: 76 (89)^b
6	1f (p-MeC6H4, c-hex)	2f: 68 (76)^b
7	1g (p-BrC6H4, c-hex)	2g: 75 (87)^b
8	1h (p-FC6H4, c-hex)	2h: 73 (82)^b
9	1i (p-CF3C6H4, c-hex)	2i: 77 (86)^b
10	1j (p-MeO2CC6H4, i-Pr)	2j: 71 (78)^b
11	1k (p-NCC6H4, i-Pr)	2k: 72 (91)^b
12	1l (p-NO2C6H4, i-Pr)	2l: 76 (89)^b
13	1m (Phenylethenyl, i-Pr)	2m: 65 (74)^b
14	1n (m-BrC6H4, i-Pr)	2n: 64 (70)^b
15	1o (1-Naphthyl, i-Pr)	2o: 78 (86)^b
16	1p (2-Phenylethyl, i-Pr)	2p: 70 (70)^b
17	1q (1-Phenylpropyl, i-Pr)	2q: 63 (75)^b
18	1r (Ph, (S)-α-Methylbenzyl)	2r: 65 (76)^b
19	1s (Ph, n-Bu)	2s: 71 (77)^b
20	1t (Ph, 2-Phenylethyl)	2t: 72 (81)^b
21	1u (n-C10H21, Bn)	2u: 74 (87)^b
22	1v (2-Thiophenyl, Bn)	2v: 65 (80)^b
23	1w (1-Adamantyl, Bn)	2w: 68 (84)^b
24	1x (Piperonyl, Bn)	2x: 56 (62)^b
25	1y (Ph, Ph)	2y: Trace (trace)^b
26	1z (Me, p-MeO2CC6H4)	2z: Trace (trace)^b
27	1aa (Ph, t-Bu)	2aa: Trace (trace)^b

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A change of the N-alkyl groups from secondary (i-Pr, c-hex) to primary did not affect the reaction (entries 19 and 20). The reaction of heteroaromatic N-benzylthiophene-2-carboxamide 1v produced amine 2v in 65% yield (entry 22). Even hindered N-benzyladamantane-1-carboxamide 1w reacted smoothly to give amine 2w in 68% yield (entry 23). The reaction also tolerated the acetal group although the corresponding amine was obtained in a modest yield (56%) (piperonamide 1x, entry 24). However, the reaction failed with N-aryl (entries 25 and 26) and N-tert-butyl amides (entry 27). Similarly, attempted selective reduction of picolinamides and 2-furoylamide were unsuccessful.

In view of the widespread use of a secondary amide as a valuable directing group for both lithiation-functionalization and C–H activation-functionalization, we next focused on the application of the present method to the reduction of C–H functionalization products.

The reduction of a Nakamura's C–H functionalization product 5^14a was first investigated. Under the standard conditions (vide supra), the reduction of 5 proceeded without incident to give 6 in 64% yield (Scheme 2). It is worth mentioning that amide 5 is also a product obtained by C–H lithiation–ethylation.^13g,h,14a Compared with the reaction of the parent amide 1a (Table 2, entry 1), the lower yield of amine 6 might be attributed to steric hindrance presented in 5. We next examined the reduction of compound 7, a Daugulis’ C–H functionalization product.^14b Subjecting 7 to the conditions that we used previously led to the desired amine 8 in 40% yield. To our delight, the yield improved to 60% by increasing the amount of NaBH₄ to 1.5 equiv. and prolonging the reduction time to 12 h. Finally, the method was applied to 9, a Dong's C–H functionalization product.^14c As expected, under the standard conditions, the reduction of amide 9 gave amine 10 in 61% yield.

Scheme 2 Reduction of selected C–H functionalization products.

We next examined the reduction of secondary lactams. Attempted reduction of secondary lactam 11, an intermediate in our recent synthesis of alkaloid (−)-streptopyrrolidine,¹⁹ to the optimized reduction conditions failed. This is in agreement with our related results.^15m The failure led us to recall Ganem's chemistry, who has demonstrated the selective reduction of secondary lactams (2-pyrrolidones) to imines^15b,c by Schwartz reagent (Cp₂ZrHCl).²⁰ It was envisaged that the presumed imine–zirconium complex could be further reduced by NaBH₄. To our delight, treatment of lactam 11 with Cp₂ZrHCl in THF at r.t. for 30 min, followed by addition of NaBH₄ (3.0 equiv.) smoothly afforded pyrrolidine 12 in an 82% yield. Similar reduction of t-butyl pyroglutamate 13 produced chemoselectively t-butyl prolinate 14 in an 80% yield (Scheme 3). The observed chemoselectivity is in agreement with those observed by Ganem.^15d

Scheme 3

Conclusion

In summary, on the basis of our preliminary results, we have developed a simple method for the direct reduction of secondary amides, which relied solely on two reagents, Tf₂O and NaBH₄. Both aromatic and aliphatic amides reacted well, and the N-alkyl group can either be primary or secondary alkyls, but the reaction failed with N-aryl and N-tert-butyl amides. The reaction exhibited good functional group tolerance for a series of reducible functional groups that ranged from halo (Cl, Br, F) to ether (OMe), from ester (CO₂Me) to cyano (CN), and from nitro (NO₂) to acetal (OCH₂O). The reduction of an α,β-unsaturated amide also ran chemoselectively at the carbonyl group. The reduction method is limited to amides. The chemoselective reduction of secondary lactams has been achieved using the Cp₂ZrHCl–NaBH₄ combination. The functionalized product may be used for further reactions such as coupling reactions. We also demonstrated that the method is applicable to the direct reduction of C–H lithiation–alkylation and C–H functionalization products. To the best of our knowledge, this is the first example of collective and direct reduction of both C–H lithiation-functionalization and C–H functionalization products, which renders the use of directing groups in the chemistry of C–H functionalization more step-economical.

Experimental section

General methods

¹H NMR and ¹³C NMR spectra were recorded on a Bruker 400 (¹H/400 MHz, ¹³C/100 MHz) spectrometer. Chemical shifts are expressed in parts per million (δ) relative to an internal standard of residual chloroform (7.26 ppm for ¹H NMR and 77.0 ppm for ¹³C NMR). Data for ¹H NMR are reported as chemical shifts (multiplicity, coupling constant, number of protons). ESI-Mass spectra were recorded on a Bruker Dalton ESquire 3000 plus LC-MS apparatus. Optical rotations were measured with an Anton Paar MCP 500 polarimeter. Melting points were determined on a Büchi M560 Automatic Melting Point apparatus. Infrared spectra were recorded with a Nicolet Avatar 330 FT-IR spectrometer using the film or KBr pellet technique.

Silica gel (300–400 mesh) was used for flash column chromatography, eluting (unless otherwise stated) with the ethyl-acetate–petroleum ether (PE) (60–90 °C) mixture. Tf₂O was distilled over phosphorus pentoxide and used within a week. THF was distilled over sodium benzophenone ketyl under N₂. Dichloromethane was distilled over calcium hydride under N₂.

General procedure A for the preparation of amines from amides

To a solution of an amide (1.0 mmol) in anhydrous CH₂Cl₂ (4 mL) was added Tf₂O (1.1 mol equiv., 1.1 mmol) in an ice bath. After being stirred for 0.5 h, NaBH₄ (1.3 mol equiv., 1.3 mmol) was added in one portion and the mixture was diluted with 2.5 mL of THF. The reaction mixture was stirred for 60 min. The reaction was quenched with H₂O (5 mL), and the pH of the reaction mixture was adjusted to 10.5–11.0 by the addition of a saturated aqueous sodium carbonate solution at 0 °C. The cooled aqueous solution was extracted with Et₂O (5 × 15 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with ethyl acetate/petroleum ether/triethylamine (1%) to afford the amine.

General procedure B for the preparation of lactams from amides

A solution of lactam (0.5 mmol) in THF (5 mL) was added dropwise to a suspension of Cp₂ZrHCl (1.6 mol equiv., 0.8 mmol, 206 mg) in THF (5 mL) at room temperature under an argon atmosphere. The mixture was stirred until the white suspension disappeared and the solution became clear. Then NaBH₄ (3.0 mol equiv., 1.5 mmol) was added in one portion at 0 °C. The mixture was warmed gradually to ambient temperature and stirred overnight. The reaction was quenched with H₂O (2 mL), and the pH of the reaction mixture was adjusted to 10.5–11.0 by the addition of a saturated aqueous sodium carbonate solution at 0 °C. The mixture was filtered through a Celite pad (washed with Et₂O). The filtrate was extracted with Et₂O (5 × 10 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with ethyl acetate–petroleum ether to afford the amine.

N-Benzylisopropylamine (2a). Following the general procedure A, the reduction of amide 1a (163 mg, 1.0 mmol) gave, after chromatographic separation eluting with EtOAc–PE (v/v = 1 : 3), the known amine^18a2a (138 mg, yield: 74%) a colourless oil. IR (film) ν_max: 3448, 2934, 2856, 1615, 1470, 1367, 1113, 707 cm⁻¹; ¹H NMR (CDCl₃, 400 MHz): δ 1.10 (d, J = 6.2 Hz, 6H, CHCH₃), 1.36 (br s, 1H, NH), 2.86 (heptet, J = 6.2 Hz, 1H, NHCH), 3.78 (s, 2H, CH₂NH), 7.21–7.27 (m, 1H, Ar–H), 7.28–7.38 (m, 4H, Ar–H) ppm; ¹³C NMR (CDCl₃, 100 MHz): δ 22.9 (2C), 48.1, 51.6, 126.8, 128.1 (2C), 128.4 (2C), 140.8 ppm; MS (ESI, m/z): 150 (M + H⁺).

N-(4-Methylbenzyl)isopropylamine (2b). Following the general procedure A, the reduction of amide 1b (177 mg, 1.0 mmol) gave, after chromatographic separation eluting with EtOAc–PE (v/v = 1 : 3), the known amine^18a2b (110 mg, yield: 67%) as a pale yellow oil. IR (film) ν_max: 3457, 2958, 2930, 2858, 1720, 1664, 1612, 1464, 1272, 1105, 823, 754 cm⁻¹; ¹H NMR (CDCl₃, 400 MHz): δ 1.09 (d, J = 6.2 Hz, 6H, CHCH₃), 1.37 (br s, 1H, NH), 2.33 (s, 3H, CH₃), 2.84 (heptet, J = 6.2 Hz, 1H, NHCH), 3.74 (s, 2H, CH₂NH), 7.12 (d, J = 7.7 Hz, 2H, Ar–H), 7.20 (d, J = 7.7 Hz, 2H, Ar–H) ppm; ¹³C NMR (CDCl₃, 100 MHz): δ 21.0, 22.9 (2C), 48.0, 51.3, 128.0 (2C), 129.0 (2C), 136.3, 137.7 ppm; MS (ESI, m/z): 164 (M + H⁺).

N-(4-Methoxybenzyl)isopropylamine (2c). Following the general procedure A, the reduction of amide 1c (193 mg, 1.0 mmol) gave, after chromatographic separation eluting with EtOAc–PE (v/v = 1 : 3), the known amine^18a,b2c (128 mg, yield: 71%) as a pale yellow oil. IR (film) ν_max: 3316, 2967, 2930, 2835, 1615, 1507, 1466, 1242, 1176, 1039, 827 cm⁻¹; ¹H NMR (CDCl₃, 400 MHz): δ 1.09 (d, J = 6.3 Hz, 6H, CHCH₃), 1.31 (br s, 1H, NH), 2.84 (heptet, J = 6.3 Hz, 1H, NHCH), 3.74 (s, 2H, CH₂NH), 3.79 (s, 3H, OCH₃), 6.77–6.94 (m, 2H, Ar–H), 7.19–7.25 (m, 2H, Ar–H) ppm; ¹³C NMR (CDCl₃, 100 MHz): δ 22.9 (2C), 47.9, 51.0, 55.2, 113.7 (2C), 129.2 (2C), 132.9, 158.5 ppm; MS (ESI, m/z): 180 (M + H⁺).

N-(4-Chlorobenzyl)isopropylamine (2d). Following the general procedure A, the reduction of amide 1d (198 mg, 1.0 mmol) gave, after chromatographic separation eluting with EtOAc–PE (v/v = 1 : 3), the known amine^18a2d (134 mg, yield: 73%) as a pale yellow oil. IR (film) ν_max: 3316, 2958, 2926, 2847, 1509, 1470, 1379, 1088, 1010, 806 cm⁻¹; ¹H NMR (CDCl₃, 400 MHz): δ 1.09 (d, J = 6.3 Hz, 6H, CHCH₃), 1.30 (br s, 1H, NH), 2.83 (heptet, J = 6.3 Hz, 1H, NHCH), 3.74 (s, 2H, CH₂NH), 7.19–7.35 (m, 4H, Ar–H) ppm; ¹³C NMR (CDCl₃, 100 MHz): δ 22.9 (2C), 48.1, 50.8, 128.4 (2C), 129.4 (2C), 132.4, 139.3 ppm; MS (ESI, m/z): 184 (M + H⁺).

N-Benzylcyclohexylamine (2e). Following the general procedure A, the reduction of amide 1e (203 mg, 1.0 mmol) gave, after chromatographic separation eluting with EtOAc–PE (v/v = 1 : 3), the known amine^12b2e (144 mg, yield: 76%) as a colourless oil. IR (film) ν_max: 3312, 3025, 2926, 2851, 1603, 1499, 1458, 1122, 1022, 736, 694 cm⁻¹; ¹H NMR (CDCl₃, 400 MHz): δ 1.10–1.31 (m, 5H, c-hex-H), 1.36 (br s, 1H, NH), 1.57–1.65 (m, 1H, c-hex-H), 1.69–1.77 (m, 2H, c-hex -H), 1.90–1.95 (m, 2H, c-hex-H), 2.45–2.52 (m, 1H, NHCH), 3.81 (s, 2H, CH₂NH), 7.21–7.25 (m, 1H, Ar–H), 7.31–7.32 (m, 4H, Ar–H) ppm; ¹³C NMR (CDCl₃, 100 MHz): δ 25.0 (2C), 26.2, 33.6 (2C), 51.0, 56.2, 126.7, 128.1 (2C), 128.4 (2C), 141.0 ppm; MS (ESI, m/z): 190 (M + H⁺).

N-(4-Methylbenzyl)cyclohexylamine (2f). Following the general procedure A, the reduction of amide 1f (218 mg, 1.0 mmol) gave, after chromatographic separation eluting with EtOAc–PE (v/v = 1 : 3), the known amine^12b2f (138 mg, yield: 68%) as a pale yellow oil. IR (film) ν_max: 3316, 2922, 2839, 1520, 1449, 1122, 806, 735 cm⁻¹; ¹H NMR (CDCl₃, 400 MHz): δ 1.09–1.29 (m, 5H, c-hex-H), 1.38 (br s, 1H, NH), 1.58–1.64 (m, 1H, c-hex-H), 1.69–1.76 (m, 2H, c-hex-H), 1.87–1.94 (m, 2H, c-hex-H), 2.33 (s, 3H, CH₃), 2.43–2.52 (m, 1H, NHCH), 3.76 (s, 2H, CH₂NH), 7.12 (d, J = 7.8 Hz, 2H, Ar–H), 7.20 (d, J = 7.8 Hz, 2H, Ar–H) ppm; ¹³C NMR (CDCl₃, 100 MHz): δ 21.0, 25.0 (2C), 26.2, 33.5 (2C), 50.7, 56.0, 128.0 (2C), 129.0 (2C), 136.2, 137.9 ppm; MS (ESI, m/z): 204 (M + H⁺).

N-(4-Bromobenzyl)cyclohexylamine (2g). Following the general procedure A, the reduction of amide 1g (141 mg, 0.5 mmol) gave, after chromatographic separation eluting with EtOAc–PE (v/v = 1 : 3), the known amine^12b2g (101 mg, yield: 75%) as a pale yellow oil. IR (film) ν_max: 3303, 2922, 2851, 1478, 1445, 1122, 1072, 806, 737 cm⁻¹; ¹H NMR (CDCl₃, 400 MHz): δ 1.05–1.30 (m, 6H, c-hex-H and NH), 1.60–1.65 (m, 1H, c-hex-H), 1.69–1.77 (m, 2H, c-hex-H), 1.84–1.93 (m, 2H, c-hex-H), 2.41–2.50 (m, 1H, NHCH), 3.76 (s, 2H, CH₂NH), 7.17–7.24 (m, 2H, Ar–H), 7.41–7.45 (m, 2H, Ar–H) ppm; ¹³C NMR (CDCl₃, 100 MHz): δ 25.0 (2C), 26.1, 33.6 (2C), 50.3, 56.1, 120.4, 129.7 (2C), 131.4 (2C), 140.1 ppm; MS (ESI, m/z): 268 and 270 (M + H⁺).

N-(4-Fluorobenzyl)cyclohexylamine (2h). Following the general procedure A, the reduction of amide 1h (114 mg, 0.5 mmol) gave, after chromatographic separation eluting with EtOAc–PE (v/v = 1 : 3), the known amine^12b2h (76 mg, yield: 73%) as a pale yellow oil. IR (film) ν_max: 3299, 2934, 2851, 1611, 1507, 1449, 1221, 1118, 835 cm⁻¹; ¹H NMR (CDCl₃, 400 MHz): δ 1.03–1.33 (m, 6H, c-hex-H and NH), 1.59–1.65 (m, 1H, c-hex-H), 1.70–1.77 (m, 2H, c-hex-H), 1.87–1.95 (m, 2H, c-hex-H), 2.41–2.50 (m, 1H, NHCH), 3.77 (s, 2H, CH₂NH), 6.90–7.04 (m, 2H, Ar–H), 7.24–7.32 (m, 2H, Ar–H) ppm; ¹³C NMR (CDCl₃, 100 MHz): δ 25.0 (2C), 26.1, 33.6 (2C), 50.3, 56.2, 115.1 (2C) (d, ²J_(C,F) = 21.3 Hz), 129.5 (2C) (d, ³J_(C,F) = 8.0 Hz), 136.7, 161.8 (d, ¹J_(C,F) = 244.4 Hz) ppm; MS (ESI, m/z): 208 (M + H⁺).

N-(4-(Trifluoromethyl)benzyl)cyclohexylamine (2i). Following the general procedure A, the reduction of amide 1i (136 mg, 0.5 mmol) gave, after chromatographic separation eluting with EtOAc–PE (v/v = 1 : 3), the known amine^12b2i (97 mg, yield: 77%) as a yellow oil. IR (film) ν_ma: 3307, 2934, 2868, 1615, 1453, 1325, 1158, 1122, 845, 823 cm⁻¹; ¹H NMR (CDCl₃, 400 MHz): δ 1.03–1.30 (m, 6H, c-hex-H and NH), 1.59–1.67 (m, 1H, c-hex-H), 1.69–1.79 (m, 2H, c-hex-H), 1.87–1.96 (m, 2H, c-hex-H), 2.43–2.52 (m, 1H, NHCH), 3.87 (s, 2H, CH₂NH), 7.44 (d, J = 8.0 Hz, 2H, Ar–H), 7.57 (d, J = 8.0 Hz, 2H, Ar–H) ppm; ¹³C NMR (CDCl₃, 100 MHz): δ 24.9 (2C), 26.1, 33.6 (2C), 50.5, 56.2, 124.3 (d, ¹J_(C,F) = 271.7 Hz), 125.2 (q, ³J_(C,F) = 3.7 Hz) (2C), 128.2 (2C), 129.0 (d, ²J_(C,F) = 32.2 Hz), 145.2 ppm; MS (ESI, m/z): 258 (M + H⁺).

Methyl 4-((isopropylamino)methyl)benzoate (2j). Following the general procedure A, the reduction of amide 1j (221 mg, 1.0 mmol) gave, after chromatographic separation eluting with EtOAc–PE (v/v = 1 : 3), amine 2j (147 mg, yield: 71%) as a pale yellow oil. IR (film) ν_max: 3312, 2971, 2880, 1731, 1603, 1433, 1267, 1105, 1026, 761 cm⁻¹; ¹H NMR (CDCl₃, 400 MHz): δ 1.10 (d, J = 6.3 Hz, 6H, CHCH₃), 1.41 (br s, 1H, NH), 2.84 (heptet, J = 6.3 Hz, 1H, NHCH), 3.84 (s, 2H, CH₂NH), 3.90 (s, 3H, COOCH₃), 7.40 (d, J = 8.0 Hz, 2H, Ar–H), 7.99 (d, J = 8.2 Hz, 2H, Ar–H) ppm; ¹³C NMR (CDCl₃, 100 MHz): δ 22.8 (2C), 48.2, 51.2, 51.9, 127.9 (2C), 128.6, 129.6 (2C), 146.2, 167.0 ppm; HRMS (ESI, m/z) calcd for [C₁₂H₁₈NO]⁺ (M + H⁺): 208.1338; found: 208.1336.

4-((Isopropylamino)methyl)benzonitrile (2k). Following the general procedure A, the reduction of amide 1k (188 mg, 1.0 mmol) gave, after chromatographic separation eluting with EtOAc–PE (v/v = 1 : 3), amine 2k (126 mg, yield: 72%) as a pale yellow oil. IR (film) ν_max: 3316, 2959, 2929, 2868, 2225, 1608, 1467, 1380, 1174, 1125, 1022, 825 cm⁻¹; ¹H NMR (CDCl₃, 400 MHz): δ 1.10 (d, J = 6.2 Hz, 6H, CHCH₃), 1.36 (br s, 1H, NH), 2.84 (heptet, J = 6.3 Hz, 1H, NHCH), 3.85 (s, 2H, CH₂NH), 7.45 (d, J = 8.1 Hz, 2H, Ar–H), 7.61 (d, J = 8.1 Hz, 2H, Ar–H) ppm; ¹³C NMR (CDCl₃, 100 MHz): δ 22.9 (2C), 48.3, 51.0, 110.6, 119.0, 128.6 (2C), 132.1 (2C), 146.6 ppm; HRMS (ESI, m/z) calcd for [C₁₁H₁₅N₂]⁺ (M + H⁺): 175.1235; found: 175.1232.

N-(4-Nitrobenzyl)isopropylamine (2l). Following the general procedure A, the reduction of amide 1l (208 mg, 1.0 mmol) gave, after chromatographic separation eluting with EtOAc–PE (v/v = 1 : 3), amine 2l (148 mg, yield: 76%) as a yellow oil. IR (film) ν_max: 3316, 2967, 2855, 1611, 1520, 1350, 1101, 802, 736 cm⁻¹; ¹H NMR (CDCl₃, 400 MHz): δ 1.11 (d, J = 6.3 Hz, 6H, CHCH₃), 1.35 (br s, 1H, NH), 2.85 (heptet, J = 6.3 Hz, 1H, NHCH), 3.90 (s, 2H, CH₂NH), 7.51 (d, J = 8.7 Hz, 2H, Ar–H), 8.17 (d, J = 8.7 Hz, 2H, Ar–H) ppm; ¹³C NMR (CDCl₃, 100 MHz): δ 22.9, 48.4, 50.8, 123.5, 128.6, 146.9, 148.8 ppm; HRMS (ESI, m/z) calcd for [C₁₀H₁₅N₂O₂]⁺ (M + H⁺): 195.1134; found: 195.1135.

(E)-N-(3-Phenylprop-2-en)isopropylamine (2m). Following the general procedure A, the reduction of amide 1m (190 mg, 1.0 mmol) gave, after chromatographic separation eluting with EtOAc–PE (v/v = 1 : 3), the known amine^18d2m (114 mg, yield: 65%) as a pale yellow oil. IR (film) ν_max: 3370, 2967, 2922, 2855, 1565, 1458, 1383, 977, 748, 690 cm⁻¹; ¹H NMR (CDCl₃, 400 MHz): δ 1.12 (d, J = 6.3 Hz, 6H, CHCH₃), 2.93 (heptet, J = 6.3 Hz, 1H, NHCH), 3.25 (br s, 1H, NH), 3.44 (dd, J = 6.5, 1.2 Hz, 2H, CH₂NH), 6.31 (dt, J = 15.8, 6.5 Hz, 1H, CH=CHCH₂), 6.54 (dt, J = 15.8, 1.2 Hz, 1H, PhCH=CHCH₂), 7.18–7.26 (m, 1H, Ar–H), 7.27–7.34 (m, 2H, Ar–H), 7.34–7.42 (m, 2H, Ar–H) ppm; ¹³C NMR (CDCl₃, 100 MHz): δ 22.5 (2C), 48.1, 49.1, 126.3 (2C), 127.4, 127.8, 128.5 (2C), 131.7, 137.0 ppm; MS (ESI, m/z): 176 (M + H⁺).

N-(3-Bromobenzyl)isopropylamine (2n). Following the general procedure A, the reduction of amide 1n (121 mg, 0.5 mmol) gave, after chromatographic separation eluting with EtOAc–PE (v/v = 1 : 3), amine 2n (73 mg, yield: 64%) as a pale yellow oil. IR (film) ν_max: 3324, 3071, 2959, 2927, 2865, 1599, 1569, 1126, 1067, 776, 690 cm⁻¹; ¹H NMR (CDCl₃, 400 MHz): δ 1.10 (d, J = 6.3 Hz, 6H, CHCH₃), 1.42 (br s, 1H, NH), 2.84 (heptet, J = 6.3 Hz, 1H, NHCH), 3.75 (s, 2H, CH₂NH), 7.15–7.21 (m, 1H, Ar–H), 7.22–7.26 (m, 1H, Ar–H), 7.34–7.40 (m, 1H, Ar–H), 7.46–7.52 (m, 1H, Ar–H) ppm; ¹³C NMR (CDCl₃, 100 MHz): δ 22.9 (2C), 48.1, 51.0, 122.5, 126.6, 129.9 (2C), 131.1, 143.3 ppm; HRMS (ESI, m/z) calcd for [C₁₀H₁₅BrN]⁺ (M + H⁺): 228.0388 and 230.0367; found: 228.0389 and 230.0369.

N-(Naphthalen-1-ylmethyl)isopropylamine (2o). Following the general procedure A, the reduction of amide 1o (214 mg, 1.0 mmol) gave, after chromatographic separation eluting with EtOAc–PE (v/v = 1 : 3), the known amine^18b2o (156 mg, yield: 78%) as a pale yellow oil. IR (film) ν_max: 3316, 3045, 2963, 2928, 2868, 2825, 1510, 1467, 1126, 1396, 1171, 802, 792, 777 cm⁻¹; ¹H NMR (CDCl₃, 400 MHz): δ 1.15 (d, J = 6.3 Hz, 6H, CHCH₃), 1.39 (br s, 1H, NH), 2.97 (heptet, J = 6.3 Hz, 1H, NHCH), 4.21 (s, 2H, CH₂NH), 7.36–7.44 (m, 1H, Ar–H), 7.44–7.56 (m, 3H, Ar–H), 7.73–7.77 (m, 1H, Ar–H), 7.82–7.87 (m, 1H, Ar–H), 8.08–8.15 (m, 1H, Ar–H) ppm; ¹³C NMR (CDCl₃, 100 MHz): δ 23.0 (2C), 48.9, 49.3, 123.5, 125.4, 125.5, 126.0 (2C), 127.6, 128.7, 131.7, 133.8, 136.3 ppm; MS (ESI, m/z): 200 (M + H⁺).

N-(3-Phenylpropan)isopropylamine (2p). Following the general procedure A, the reduction of amide 1p (191 mg, 1.0 mmol) gave, after chromatographic separation eluting with EtOAc–PE (v/v = 1 : 3), the known amine^11e2p (124 mg, yield: 70%) as a colourless oil. IR (film) ν_max: 3312, 2967, 2835, 1578, 1569, 1112, 1014, 803, 694 cm⁻¹; ¹H NMR (CDCl₃, 400 MHz): δ 1.36 (d, J = 6.5 Hz, 6H, CHCH₃), 2.16–2.25 (m, 2H, CH₂CH₂CH₂), 2.65 (t, J = 7.5 Hz, 2H, CH₂CH₂CH₂), 2.81–2.87 (m, 2H, CH₂CH₂NH), 3.20 (heptet, J = 6.5 Hz, 1H, NHCH), 7.15–7.20 (m, 3H, Ar–H), 7.24–7.29 (m, 2H, Ar–H) ppm; ¹³C NMR (CDCl₃, 100 MHz): δ 19.4 (2C), 27.8, 32.9, 44.3, 50.2, 126.2, 128.3 (2C), 128.5 (2C), 140.1 ppm; MS (ESI, m/z): 178 (M + H⁺).

N-(3-(2-Phenylbutyl)benzyl)isopropylamine (2q). Following the general procedure A, the reduction of amide 1q (205 mg, 1.0 mmol) gave, after chromatographic separation eluting with EtOAc–PE (v/v = 1 : 2), amine 2q (121 mg, yield: 63%) as a pale yellow oil. IR (film) ν_max: 3436, 2958, 2917, 2849, 1578, 1462, 1258, 1114, 1012, 802, 694 cm⁻¹; ¹H NMR (CDCl₃, 400 MHz): δ 0.80 (t, J = 7.5 Hz, 3H), 0.95 (d, J = 6.3 Hz, 3H), 1.00 (d, J = 6.3 Hz, 3H, CH₃CH₂), 1.19 (br s, 1H, NH), 1.51–1.60 (m, 1H, CH₃CH₂), 1.66–1.75 (m, 1H, CH₃CH₂), 2.62–2.78 (m, 3H, CH₂NH and CH₂CHCH₂), 2.85–2.93 (m, 1H, NHCH), 7.14–7.25 (m, 3H, Ar–H), 7.27–7.33 (m, 2H, Ar–H) ppm; ¹³C NMR (CDCl₃, 100 MHz): δ 12.0, 22.7, 22.8, 27.6, 47.9, 48.5, 53.0, 126.3, 127.8 (2C), 128.4 (2C), 143.8 ppm; HRMS (ESI, m/z) calcd for [C₁₃H₂₂N]⁺ (M + H⁺): 192.1752; found: 192.1750.

(S)-N-Benzyl-α-methylbenzylamine (2r). Following the general procedure A, the reduction of amide 1r (225 mg, 1.0 mmol) gave, after chromatographic separation eluting with EtOAc–PE (v/v = 1 : 3), the known amine^18e2r (137 mg, yield: 65%) as a pale yellow oil. IR (film) ν_max: 3332, 3029, 2959, 2926, 2843, 1603, 1503, 1449, 1358, 761, 699 cm⁻¹; ¹H NMR (CDCl₃, 400 MHz): δ 1.37 (dd, J = 6.6, 0.8 Hz, 3H, CHCH₃), 1.71 (br s, 1H, NH), 3.59 (d, J = 13.1 Hz, 1H, CH₂NH), 3.66 (d, J = 13.1 Hz, 1H, CH₂NH), 3.81 (q, J = 6.7 Hz, 1H, NHCH), 7.20–7.40 (m, 10H, Ar–H) ppm; ¹³C NMR (CDCl₃, 100 MHz): δ 24.5, 51.6, 57.5, 126.7 (2C), 126.8, 126.9, 128.1 (2C), 128.3 (2C), 128.4 (2C), 140.6, 145.5 ppm; MS (ESI, m/z): 212 (M + H⁺).

N-Benzyl-n-butylamine (2s). Following the general procedure A, the reduction of amide 1s (177 mg, 1.0 mmol) gave, after chromatographic separation eluting with EtOAc–PE (v/v = 1 : 3), the known amine^18f2s (116 mg, yield: 71%) as a pale yellow oil. IR (film) ν_max: 3316, 3063, 2955, 2918, 2851, 1603, 1499, 1462, 1130, 740, 694 cm⁻¹; ¹H NMR (CDCl₃, 400 MHz): δ 0.91 (t, J = 7.3 Hz, 3H, CH₂CH₃), 1.30–1.40 (m, 2H, CH₂CH₂CH₃), 1.43 (br s, 1H, NH), 1.46–1.54 (m, 2H, CH₂CH₂CH₃), 2.63 (t, J = 7.3 Hz, 2H, NHCH₂CH₂), 3.78 (s, 2H, CH₂NH), 7.21–7.28 (m, 1H, Ar–H), 7.28–7.34 (m, 4H, Ar–H) ppm; ¹³C NMR (CDCl₃, 100 MHz): δ 14.0, 20.4, 32.2, 49.2, 54.1, 126.8, 128.1 (2C), 128.3 (2C), 140.5 ppm; MS (ESI, m/z): 164 (M + H⁺).

N-Benzyl-2-phenethylamine (2t). Following the general procedure A, the reduction of amide 1t (225 mg, 1.0 mmol) gave, after chromatographic separation eluting with EtOAc–PE (v/v = 1 : 3), the known amine^12d2t (153 mg, yield: 72%) as a pale yellow oil. IR (film) ν_max: 3324, 3063, 3021, 2926, 2851, 2818, 1599, 1503, 1449, 1122, 1035, 753, 694 cm⁻¹; ¹H NMR (CDCl₃, 400 MHz): δ 1.55 (br s, 1H, NH), 2.80–2.86 (m, 2H, NHCH₂CH₂), 2.88–2.93 (m, 2H, NHCH₂CH₂), 3.80 (s, 2H, CH₂NH), 7.17–7.25 (m, 4H, Ar–H), 7.25–7.33 (m, 6H, Ar–H) ppm; ¹³C NMR (CDCl₃, 100 MHz): δ 36.3, 50.5, 53.8, 126.1, 126.9, 128.0 (2C), 128.3 (2C), 128.4 (2C), 128.7 (2C), 140.0, 140.2 ppm; MS (ESI, m/z): 212 (M + H⁺).

N-Undecyl-benzylamine (2u). Following the general procedure A, the reduction of amide 1u (276 mg, 1.0 mmol) gave, after chromatographic separation eluting with EtOAc–PE (v/v = 1 : 3), the known amine^18d2u (192 mg, yield: 74%) as a colourless oil. IR (film) ν_max: 3320, 2934, 2851, 1487, 1458, 1122, 732, 693 cm⁻¹; ¹H NMR (CDCl₃, 400 MHz): δ 0.88 (t, J = 7.0 Hz, 3H, CH₂CH₃), 1.23–1.32 (m, 16H, CH₂(CH₂)₈CH₂), 1.42 (br s, 1H, NH), 1.47–1.54 (m, 2H, CH₂CH₂CH₃), 2.62 (t, J = 7.3 Hz, 2H, NHCH₂CH₂), 3.78 (s, 2H, NHCH₂), 7.22–7.27 (m, 1H, Ar–H), 7.32 (m, 4H, Ar–H) ppm; ¹³C NMR (CDCl₃, 100 MHz): δ 14.1, 22.7, 27.4, 29.3, 29.6 (4C), 30.1, 31.9, 49.5, 54.1, 126.8, 128.1 (2C), 128.3 (2C), 140.6 ppm; MS (ESI, m/z): 262 (M + H⁺).

N-(2-Thiophenylmethyl)-benzylamine (2v). Following the general procedure A, the reduction of amide 1v (109 mg, 0.5 mmol) gave, after chromatographic separation eluting with EtOAc–PE (v/v = 1 : 3), the known amine^12e2v (66 mg, yield: 65%) as a pale yellow oil. IR (film) ν_max: 3320, 3026, 2919, 2849, 1453, 1263, 1107, 735, 699 cm⁻¹; ¹H NMR (CDCl₃, 400 MHz): δ 1.76 (br s, 1H, NH), 3.83 (s, 2H, NHCH₂), 3.99 (s, 2H, CH₂NH), 6.87–7.00 (m, 2H, Ar–H), 7.20–7.28 (m, 2H, Ar–H), 7.29–7.39 (m, 4H, Ar–H) ppm; ¹³C NMR (CDCl₃, 100 MHz): δ 47.5, 52.7, 124.3, 124.8, 126.6, 127.0, 128.2 (2C), 128.4 (2C), 140.0, 144.2 ppm; MS (ESI, m/z): 204 (M + H⁺).

N-(2-Adamantanylmethyl)-benzylamine (2w). Following the general procedure A, the reduction of amide 1w (135 mg, 0.5 mmol) gave, after chromatographic separation eluting with EtOAc–PE (v/v = 1 : 3), amine 2w (87 mg, yield: 68%) as a pale yellow oil. IR (film) ν_max: 3361, 3026, 2905, 2846, 1494, 1452, 1107, 733, 697 cm⁻¹; ¹H NMR (CDCl₃, 400 MHz): δ 1.51–1.55 (m, 6H, CHCH₂CH and NH), 1.61–1.67 (m, 4H, CHCH₂CH), 1.69–1.74 (m, 3H, CHCH₂CH), 1.97 (m, 3H, CH₂CHCH₂), 2.25 (s, 2H, CH₂NH), 3.79 (s, 2H, NHCH₂), 7.21–7.26 (m, 1H, Ar–H), 7.29–7.35 (m, 4H, Ar–H) ppm; ¹³C NMR (CDCl₃, 100 MHz): δ 28.5 (3C), 33.5, 37.3 (3C), 40.9 (3C), 54.7, 62.2, 126.7, 127.9 (2C), 128.3 (2C), 141.0 ppm; HRMS (ESI, m/z) calcd for [C₁₈H₂₆N]⁺ (M + H⁺): 256.2065; found: 256.2061.

N-(2-(Benzo[d][1,3]dioxol-5-yl)methyl)-benzylamine (2x). Following the general procedure A, the reduction of amide 1x (128 mg, 0.5 mmol) gave, after chromatographic separation eluting with EtOAc–PE (v/v = 1 : 3), the known amine^12e2x (68 mg, yield: 56%) as a pale yellow oil. IR (film) ν_max: 3336, 3021, 2916, 2849, 1607, 1501, 1495, 1441, 1246, 807, 736, 698 cm⁻¹; ¹H NMR (CDCl₃, 400 MHz): δ 1.64 (br s, 1H, NH), 3.71 (s, 2H, CH₂NH), 3.78 (s, 2H, NHCH₂), 5.92 (s, 2H, OCH₂O), 6.73–6.80 (m, 2H, Ar–H), 6.86 (s, 1H, Ar–H), 7.23–7.28 (m, 1H, Ar–H), 7.29–7.37 (m, 4H, Ar–H) ppm; ¹³C NMR (CDCl₃, 100 MHz): δ 52.9 (2C), 100.8, 108.0, 108.7, 121.2, 126.9, 128.1 (2C), 128.4 (2C), 134.3, 140.3, 146.5, 147.7 ppm; MS (ESI, m/z): 242 (M + H⁺).

N-(o-Ethylbenzyl)isopropylamine (6). Following the general procedure A, the reduction of amide 5 (96 mg, 0.5 mmol) gave, after chromatographic separation eluting with EtOAc–PE (v/v = 1 : 3), amine 6 (56 mg, yield: 64%) as a pale yellow oil. IR (film) ν_max: 3312, 2971, 2934, 2855, 1462, 1453, 1375, 1179, 735 cm⁻¹; ¹H NMR (CDCl₃, 400 MHz): δ 1.12 (d, J = 6.3 Hz, 6H, CHCH₃), 1.24 (t, J = 7.6 Hz, 3H, CH₂CH₃), 1.36 (br s, 1H, NH), 2.71 (q, J = 7.6 Hz, 2H, CH₂CH₃), 2.89 (heptet, J = 6.3 Hz, 1H, NHCH), 3.77 (s, 2H, CH₂NH), 7.14–7.22 (m, 3H, Ar–H), 7.30 (d, J = 7.1 Hz, 1H, Ar–H) ppm; ¹³C NMR (CDCl₃, 100 MHz): δ 15.4, 23.0 (2C), 25.3, 48.7, 48.8, 125.9, 127.1, 128.5, 128.8, 138.0, 142.2 ppm; HRMS (ESI, m/z) calcd for [C₁₂H₂₀N]⁺ (M + H⁺): 178.1596; found: 178.1596.

N-[4-Bromo-3′-(trifluoromethoxy)]-[1,1′-biphenyl]-3-yl)meth-yl)isopropylamine (8). Following the general procedure A, the reduction of amide 7 (201 mg, 0.5 mmol) gave, after chromatographic separation eluting with EtOAc–PE (v/v = 1 : 3), amine 8 (116 mg, yield: 60%) as a pale yellow oil. IR (film) ν_max: 3324, 3054, 2965, 2929, 1610, 1588, 1470, 1375, 1259, 1168, 794, 702, 636 cm⁻¹; ¹H NMR (CDCl₃, 400 MHz): δ 0.96 (d, J = 6.3 Hz, 6H, CHCH₃), 1.36 (br s, 1H, NH), 2.67 (heptet, J = 6.3 Hz, 1H, NHCH), 3.64 (s, 2H, CH₂NH), 7.10 (d, J = 8.1 Hz, 1H, Ar–H), 7.22–7.26 (m, 1H, Ar–H), 7.28–7.33 (m, 2H, Ar–H), 7.41–7.48 (m, 2H, Ar–H), 7.64 (m, 1H, Ar–H) ppm; ¹³C NMR (CDCl₃, 100 MHz): δ 22.7 (2C), 48.4, 48.7, 119.2, 119.8, 121.6, 121.8, 122.2, 127.4, 129.6, 130.1, 131.4, 132.3, 139.0, 140.3, 142.1, 149.1 ppm; HRMS (ESI, m/z) calcd for [C₁₇H₁₈BrF₃NO]⁺ (M + H⁺): 388.0524 and 390.0503; found: 388.0512 and 390.0503.

N-((2′,6′-Biphenyl)phenethyl)isopropylamine (10). Following the general procedure A, the reduction of amide 9 (165 mg, 0.5 mmol) gave, after chromatographic separation eluting with EtOAc–PE (v/v = 1 : 3), amine 10 (96 mg, yield: 61%) as a pale yellow oil. IR (film) ν_max: 3328, 3056, 2962, 2867, 1499, 1457, 1171, 760, 702 cm⁻¹; ¹H NMR (CDCl₃, 400 MHz): δ 0.69 (d, J = 6.3 Hz, 6H, CHCH₃), 0.91 (br s, 1H, NH), 2.28–2.40 (m, 3H, CH₂CH₂ and NH), 2.69–2.76 (m, 2H, CH₂CH₂NH), 7.16–7.22 (m, 2H, Ar–H), 7.23–7.29 (m, 1H, Ar–H), 7.31–7.44 (m, 10H, Ar–H) ppm; ¹³C NMR (CDCl₃, 100 MHz): δ 22.6 (2C), 30.9, 47.1, 47.2, 125.3, 126.9 (2C), 128.1 (4C), 129.2 (4C), 129.4 (2C), 135.3 (2C), 142.2 (2C), 142.9 ppm; HRMS (ESI, m/z) calcd for [C₂₃H₂₆N]⁺ (M + H⁺): 316.2065; found: 316.2062.

(2S,3S)-2-Benzyl-3-(benzyloxy)pyrrolidine (12). Following the general procedure B, the reduction of lactam 11 (100 mg, 0.36 mmol) gave, after chromatographic separation eluting with EtOAc–PE (v/v = 1 : 5), pyrrolidine 12 (80 mg, yield: 82%) as a colourless oil. [α]²⁰_D +152.7 (c 1.0, CHCl₃); IR (film) ν_max: 3440, 3034, 2926, 2872, 1495, 1453, 1180, 1047, 740, 707 cm⁻¹; ¹H NMR (CDCl₃, 400 MHz): δ 1.84–1.93 (m, 1H, OCHCH₂CH₂), 2.00–2.09 (m, 1H, OCHCH₂CH₂), 2.87–3.14 (m, 3H, NHCH₂ and PhCH₂CH), 3.38–3.46 (dd, J = 12.1, 3.1 Hz, 1H, PhCH₂CH), 3.46–3.56 (m, 1H, NHCH), 3.79 (t, J = 3.4 Hz, 1H, OCHCH₂), 3.98 (br s, 1H, NH), 4.30 (d, J = 11.3 Hz, 1H, OCH₂Ph), 4.50 (d, J = 11.3 Hz, 1H, OCH₂Ph), 7.16–7.43 (m, 10H, Ar–H) ppm; ¹³C NMR (CDCl₃, 100 MHz): δ 27.7, 31.9, 53.0, 70.6, 72.3, 77.7, 126.6, 127.8, 128.0, 128.6 (2C), 129.1, 137.4, 137.9 ppm; HRMS (ESI, m/z) calcd for [C₁₈H₂₁NNaO]⁺ (M + Na⁺): 290.1521; found: 290.1510.

tert-Butyl (S)-pyrrolidine-2-carboxylate (14). Following the general procedure B, the reduction of lactam 13 (100 mg, 0.54 mmol) gave, after chromatographic separation eluting with EtOAc–PE (v/v = 1 : 20), the known proline derivative^18g,h14 (75 mg, yield: 80%) as a white solid. Mp: 88–89 °C (EtOAc–hexane); [α]²⁰_D −47.6 (c 1.0, CHCl₃ {lit.¹⁸ⁱ [α]²⁴_D −40.5 (c 0.4, MeOH)}. IR (film) ν_max: 3443, 2980, 2930, 1727, 1379, 1180, 1159 cm⁻¹; ¹H NMR (CDCl₃, 400 MHz): δ 1.49 (s, 9H, CH₃), 1.75–1.83 (m, 1H, CH₂CH₂CH₂), 1.89–1.98 (m, 1H, CH₂CH₂CH₂), 2.00–2.11 (m, 1H, CH₂CH₂CH), 2.29–2.41 (m, 1H, CH₂CH₂CH), 2.87–2.98 (m, 1H, CH₂CH₂NH), 3.33–3.42 (m, 1H, CH₂CH₂NH), 3.63–3.71 (m, 1H, COCHNH), 4.98 (br s, 1H, NH) ppm; ¹³C NMR (CDCl₃, 100 MHz): δ 24.8, 27.9 (3C), 30.0, 54.9, 67.3, 83.6, 171.2 ppm; HRMS (ESI, m/z) calcd for [C₉H₁₇NNaO₂]⁺ (M + Na⁺): 194.1157; found: 194.1150.

Acknowledgements

The authors are grateful to the Natural Science Foundation of China (NSFC, grant no. 21332007), and the Program for Changjiang Scholars and Innovative Research Team in the University of the Ministry of Education of China for financial support.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: ¹H and ¹³C NMR spectra of all reduction products. See DOI: 10.1039/c4qo00317a

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