Direct transformation of amides: a one-pot reductive Ugi-type three-component reaction of secondary amides

Abstract

Amides are a class of highly stable carbonyl compounds, which are widely used as reliable synthetic intermediates in both organic synthesis and pharmaceutical chemistry. Thus, the direct transformation of amides into other classes of compounds under mild reaction conditions is highly desirable and in the meantime challenging. An efficient reductive Ugi-type reaction has been established. The method employs common secondary amides as starting materials. The reaction exhibited a broad substrate scope, good chemoselectivity and functional group tolerance and provides rapid access to a variety of functionalized α-acetamidoamides.

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Introduction

Amides are widely used as reliable synthetic intermediates in both organic synthesis and pharmaceutical chemistry.^1–4 In this context, at a later stage of a synthetic route, mild and chemoselective transformation of an amide intermediate into another class of compound is indispensable. However, due to the high stability of amides, most of the known transformations require harsh conditions that are of low functional group tolerance.³ Thus, indirect methods based on additional synthetic procedures are commonly adopted.⁴ The prior transformation of amides to thioamides, followed by S-methylation and reductive alkylation,^4b,c,d,g or followed by Eschenmoser sulfide contraction^4a,h are the two methods that find widespread applications in alkaloid synthesis.

With the current interest to develop step-economical⁵ and sustainable organic synthesis,⁶ in recent years, the direct, chemoselective, and versatile transformation of amides into other classes of compounds at lower oxidation states has attracted considerable attention.⁷ Tremendous effort has been devoted to the direct reduction of amides to give amines.⁸ Significant progress has also been made on the direct transformation of amides into alcohols,⁹ imines/aldehydes,¹⁰ and enamines.¹¹ Moreover, exciting progress has been achieved in recent years on the use of amides as starting materials for the formation of C–C bonds.^12–22 The Vilsmeier–Haack¹²- and Bischler–Napieralski¹³-type cyclization reactions, direct heteroaromatization,¹⁴ reductive functionalization^15,16/bis-alkylation¹⁷/coupling,¹⁸ and deaminative alkylation¹⁹ of amides, amide-based rearrangements,²⁰ as well as the reductive nitro-Mannich cyclization of amides²¹ have been documented. The power of such transformations has been demonstrated by the highly efficient total synthesis of Kopsia alkaloids,²²Aspidosperma alkaloids,^13b gephyrotoxin,^16f and manzamine A.^21b However, a method for the direct transformation of common amides to other classes of N-containing compounds is still highly demanding and remains a formidable challenge. Thus, the merging of the concept of direct transformation of amides with other powerful synthetic methodologies to provide other class of N-containing compounds is highly desirable.

The Ugi four- and three-component reactions²³ (Scheme 1) are powerful tools in combinatorial chemistry,²⁴ total synthesis of natural products,^23g,h,25 and medicinal chemistry.^23g,26 To further improve the synthetic utility and sustainability⁶ of this powerful reaction, much effort has been devoted to develop new protocols that employ stable starting materials to replace imines and aldehydes. A number of Ugi-type reactions have been reported.²⁷As part of our research program directed toward the development of C–C bond forming reactions starting from common amides,^{15a,b,e–i,17a,c,18,19b} we report herein the first Ugi-type multi-component reaction utilizing common secondary amides as a component.²⁸

Scheme 1 The Ugi-4CR/3CR and Ugi-type reaction based on amides.

Results and discussion

We have previously reported a one-pot reductive cross-coupling of secondary amides with ketones.¹⁸ In that method, trifluoromethanesulfonic anhydride (Tf₂O)/2-fluoropyridine (2-F-Py) –Et₃SiH –NEt₃ combination turned out to be effective for generating imine A suitable for the C–C bond forming reaction (Scheme 2). It was envisaged that the in situ generated imine A could also participate in a Ugi-type three-component reaction. It has been reported that the Ugi-type reactions are sensitive to reaction conditions.^27f,l The major challenge in attempting an amide-based reductive Ugi-type reaction resided in the compatibility of the reaction conditions for the amide-activation step with those for the one-pot Ugi-type reaction (Scheme 2).

Scheme 2 The compatibility of the reaction conditions for the amide-activation step with those of the subsequent steps.

At the outset of our investigation, our previous reaction conditions were adopted.¹⁸ Hence, 1a was treated sequentially with trifluoromethanesulfonic anhydride²⁹ (1.3 equiv.) and 2-fluoropyridine³⁰ (1.5 equiv.) in CH₂Cl₂ at 0 °C for 10 min, and triethylsilane³¹ (1.1 equiv.) at 0 °C to RT for 5 h. The solvent was then removed and the residue was dissolved in trifluoroethanol (TFE).^27l Triethylamine (2.0 equiv.), acetic acid (2.0 equiv.) and cyclohexyl isocyanide (c-hexNC, 1.2 equiv.) were added sequentially and the reaction was then stirred for 12 h. To our delight, under such conditions, the desired product α-acetamidoamide 2a was obtained in 88% yield (Table 1, entry 1). Varying the amount of triethylamine (entries 2–4) or the use of other bases such as the Hünig base or DBU (entries 5 and 6) did not improve the yield.

Table 1 Optimization of the reaction conditions for the one-pot reductive Ugi-type reaction of amide 1a

Entry	Base (equiv.)	Equiv. of MeCO2H	Solvent	Yield^a (%)
a Isolated yield. DBU = 1,8-diazabicyclo(5.4.0)undec-7-ene.
1	Et3N (2.0)	2.0	CF3CH2OH	88
2	Et3N (1.0)	2.0	CF3CH2OH	22
3	Et3N (3.0)	2.0	CF3CH2OH	82
4	Et3N (5.0)	2.0	CF3CH2OH	46
5	i-PrNEt2 (2.0)	2.0	CF3CH2OH	73
6	DBU (2.0)	2.0	CF3CH2OH	68
7	Et3N (2.0)	1.0	CF3CH2OH	63
8	Et3N (2.0)	3.0	CF3CH2OH	82
9	Et3N (2.0)	5.0	CF3CH2OH	69
10	Et3N (2.0)	2.0	CH2Cl2	57
11	Et3N (2.0)	2.0	MeOH/CH2Cl2	70
12	Et3N (2.0)	2.0	MeOH	76

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Equal amounts of AcOH and Et₃N (both 2.0 equiv., entry 1) seemed to be the most efficient combination. Either lowering or increasing the amount of AcOH led to inferior results (entries 7–9), suggesting that maintaining a suitable pH is critical for an efficient reaction. Other solvents such as CH₂Cl₂ or methanol or a combination of the two were also tested for the Ugi-type reaction but were found to be less efficient than TFE (entries 10–12).

With the optimal conditions for the reductive Ugi-type reaction of secondary amides defined, the scope of the one-pot reaction was explored (Table 2). The reaction tolerated both moderate electron-donating groups (Me) and electron-withdrawing groups at the benzoyl moiety of amides (entries 1–5). However, with p-methoxybenzamide as a substrate, the desired Ugi-adduct 2f was isolated in only 28% (entry 6) along with p-methoxybenzaldehyde. It seemed that the p-methoxybenzimine formed during the reaction was not an effective coupling partner and was probably hydrolyzed during the aqueous workup to give the aldehyde. The use of more equivalents of isocyanide or a prolonged reaction time did not increase the yield. 1-Naphthamide 1g also reacted to give the desired 2g in 81% yield (entry 7). Notably, the reactions of aliphatic amides 1h–k also proceeded smoothly to give the desired products 2h–k in moderate to good yields (entries 8–11). Amides with primary alkyl N-substituents (1l–n) were also suitable substrates and produced the desired α-acetamidoamides albeit in moderate yields (entries 12–14).

Table 2 Scope and limitation of the one-pot reductive Ugi-type reaction of secondary amides

Entry; Product (%Yield)^a

a Isolated yield. b The reduction with Et₃SiH was performed at 0 °C.

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We next turned our attention to the chemoselectivity of the reaction. To our delight, the reaction tolerated several sensitive groups, including aromatic ester, cyano, nitro, ketone and aldehyde groups (entries 15–19, 47–86% yields). The latter two groups are usually incompatible with the known Ugi reactions and Ugi-type reactions.

Conclusion

In summary, we have developed an efficient reductive Ugi-type three-component reaction, which features the use of readily available and stable common secondary amides as a component. The reaction tolerated a wide range of substituents on the amides and various functionalized α-acetamidoamides have been synthesized. In view of the widespread use of secondary amides in organic synthesis and medicinal chemistry, their direct transformation into α-acetamidoamides is of great significance.

Experimental section

General methods

Melting points were uncorrected and determined on a Büchi M560 Automatic Melting Point apparatus. ¹H NMR and ¹³C NMR spectra were recorded on a Bruker 400 (¹H/400 MHz, ¹³C/100 MHz) or Bruker 500 (¹H/500 MHz, ¹³C/126 MHz) spectrometer, respectively. Chemical shifts (δ) are reported in ppm and respectively referenced 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). HRFABMS spectra were recorded on a 7.0 T FT-MS. 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 (FC), eluting with an ethyl acetate/hexane mixture. Trifluoromethanesulfonic anhydride (Tf₂O) was distilled over phosphorus pentoxide and was stored for no more than a week before re-distillation. Dry dichloromethane was distilled over calcium hydride under an argon atmosphere. All reactions were carried out under an argon atmosphere.

General procedure for the one-pot reductive Ugi-type three-component reaction of secondary amides 1

To a cooled (0 °C) solution of secondary amide 1 (0.50 mmol, 1.0 equiv.) and 2-fluoropyridine (65 μL, 0.75 mmol, 1.5 equiv.) in CH₂Cl₂ (5 mL) were added dropwise Tf₂O (110 μL, 0.65 mmol, 1.3 equiv.) and Et₃SiH (88 μL, 0.55 mmol, 1.1 equiv.). The reaction mixture was warmed to RT and stirred for 5 h. The solvent was removed through a drying tube charged with anhydrous CaCl₂ under reduced pressure. To the concentrate was added 5 mL of CF₃CH₂OH. To the resulting mixture were added sequentially Et₃N (140 μL, 1.00 mmol, 2.0 equiv.), AcOH (60 μL, 1.00 mmol, 2.0 equiv.), and cyclohexyl isocyanide (c-hexNC, 75 μL, 0.60 mmol, 1.2 equiv.). After being stirred for 12 h at RT, the mixture was concentrated under reduced pressure. The residue was taken with ethyl acetate and washed with sat. NaHCO₃ and brine. The combined organic phases were dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel eluting with EtOAc/hexane to afford the desired α-acylamino carboxamide 2.

N-Cyclohexyl-2-(N-isopropylacetamido)-2-phenylacetamide (2a)

Following the general procedure, the reduction of amide 1a (82 mg, 0.5 mmol) gave, after flash column chromatography on silica gel (eluent: EtOAc/hexane = 1/10), the desired product 2a (139 mg, 88%) as a white solid. Mp: 153–155 °C (solvent: MeOH). IR (film) ν_max 3293, 3062, 2929, 2852, 1684, 1654, 1626, 1542, 1496, 1449, 1367, 1309, 1201, 1031, 891 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 1.00–1.13 (m, 3H), 1.09 (d, J = 6.7 Hz, 3H), 1.23–1.40 (m, 2H), 1.37 (d, J = 6.7 Hz, 3H), 1.46–1.61 (m, 3H), 1.78–1.88 (m, 2H), 2.18 (s, 3H), 3.69–3.83 (m, 1H), 4.13 (septet, J = 6.7 Hz, 1H), 4.79 (s, 1H), 6.34 (d, J = 6.4 Hz, 1H), 7.22–7.33 (m, 5H); ¹³C NMR (100 MHz, CDCl₃) δ 21.0, 21.2, 22.7, 24.5, 24.6, 25.4, 32.4, 32.5, 48.2, 50.7, 62.3, 127.6 (2C), 128.5 (3C), 137.0, 169.7, 170.7; HRMS (ESI) calcd for [C₁₉H₂₈N₂O₂ + Na⁺]: 339.2048, found: 339.2053.

N-Cyclohexyl-2-(N-isopropylacetamido)-2-(p-tolyl)acetamide (2b)

Following the general procedure, the reduction of amide 1b (89 mg, 0.5 mmol) gave, after flash column chromatography on silica gel (eluent: EtOAc/hexane = 1/10), the desired product 2b (131 mg, 79%) as a white solid. Mp: 166–168 °C (solvent: MeOH). IR (film) ν_max 3421, 3296, 3055, 2930, 2854, 1684, 1654, 1624, 1542, 1514, 1448, 1368, 1310, 1273, 1201, 1129 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 1.00–1.13 (m, 3H), 1.08 (d, J = 6.7 Hz, 3H), 1.24–1.39 (m, 2H), 1.36 (d, J = 6.7 Hz, 3H), 1.47–1.62 (m, 3H), 1.77–1.88 (m, 2H), 2.17 (s, 3H), 2.30 (s, 3H), 3.69–3.81 (m, 1H), 4.12 (septet, J = 6.7 Hz, 1H), 4.75 (s, 1H), 6.28 (d, J = 7.4 Hz, 1H), 7.10 (d, J = 7.9 Hz, 2H), 7.19 (d, J = 7.9 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 21.0 (2C), 21.2, 22.7, 24.5, 24.6, 25.5, 32.5, 32.6, 48.2, 50.7, 62.1, 127.6 (2C), 129.2 (2C), 134.0, 137.2, 169.8, 170.6; HRMS (ESI) calcd for [C₂₀H₃₀N₂O₂ + Na⁺]: 353.2205, found: 353.2204.

2-(4-Chlorophenyl)-N-cyclohexyl-2-(N-isopropylacetamido)acetamide (2c)

Following the general procedure, the reduction of amide 1c (99 mg, 0.5 mmol) gave, after flash column chromatography on silica gel (eluent: EtOAc/hexane = 1/10), the desired product 2c (138 mg, 79%) as a white solid. Mp: 172–174 °C (solvent: MeOH). IR (film) ν_max 3296, 3060, 2930, 2855, 1654, 1540, 1493, 1442, 1366, 1313, 1194, 1093, 1015, 827 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 0.99–1.12 (m, 3H), 1.08 (d, J = 6.4 Hz, 3H), 1.21–1.34 (m, 2H), 1.32 (d, J = 6.4 Hz, 3H), 1.44–1.60 (m, 3H), 1.75–1.83 (m, 2H), 2.14 (s, 3H), 3.66–3.77 (m, 1H), 4.10 (septet, J = 6.4 Hz, 1H), 4.73 (s, 1H), 6.45 (d, J = 7.4 Hz, 1H), 7.17–7.25 (m, 4H); ¹³C NMR (100 MHz, CDCl₃) δ 20.9, 21.0, 22.6, 24.4 (2C), 25.3, 32.3, 32.4, 48.2, 50.7, 61.7, 128.5 (2C), 128.7 (2C), 133.2, 135.4, 169.3, 170.8; HRMS (ESI) calcd for [C₁₉H₂₇ClN₂O₂ + Na⁺]: 373.1659, found: 373.1658.

2-(2-Chlorophenyl)-N-cyclohexyl-2-(N-isopropylacetamido)acetamide (2d)

Following the general procedure, the reduction of amide 1d (99 mg, 0.5 mmol) gave, after flash column chromatography on silica gel (eluent: EtOAc/hexane = 1/10), the desired product 2d (158 mg, 90%) as a colorless gummy. IR (film) ν_max 3286, 3065, 2927, 2854, 1652, 1541, 1439, 1371, 1319, 1201, 1134, 1036, 892, 748 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 0.89 (d, J = 6.7 Hz, 3H), 0.95–1.12 (m, 3H), 1.26–1.34 (m, 2H), 1.43 (d, J = 6.7 Hz, 3H), 1.48–1.60 (m, 3H), 1.77–1.91 (m, 2H), 2.23 (s, 3H), 3.68–3.83 (m, 1H), 4.10 (septet, J = 6.7 Hz, 1H), 5.11 (d, J = 7.4 Hz, 1H), 5.15 (s, 1H), 7.26–7.32 (m, 2H), 7.37–7.43 (m, 1H), 7.55–7.65 (m, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 20.7, 21.3, 22.5, 24.6, 24.7, 25.5, 32.6 (2C), 48.5, 50.6, 58.6, 127.6, 129.5, 129.6, 130.4, 133.9, 135.2, 167.2, 171.0; HRMS (ESI) calcd for [C₁₉H₂₇ClN₂O₂ + Na⁺]: 373.1659, found: 373.1655.

N-Cyclohexyl-2-(N-isopropylacetamido)-2-(4-(trifluoromethyl)-phenyl)acetamide (2e)

Following the general procedure, the reduction of amide 1e (116 mg, 0.5 mmol) gave, after flash column chromatography on silica gel (eluent: EtOAc/hexane = 1/10), the desired product 2e (136 mg, 71%) as a white solid. Mp: 124–126 °C (solvent: MeOH). IR (film) ν_max 3298, 3060, 2933, 2855, 1655, 1628, 1542, 1370, 1327, 1165, 1125, 1018 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 1.03–1.20 (m, 3H), 1.18 (d, J = 6.7 Hz, 3H), 1.25–1.40 (m, 2H), 1.37 (d, J = 6.7 Hz, 3H), 1.48–1.66 (m, 3H), 1.79–1.89 (m, 2H), 2.20 (s, 3H), 3.70–3.86 (m, 1H), 4.18 (septet, J = 6.7 Hz, 1H), 4.86 (s, 1H), 6.79 (d, J = 7.4 Hz, 1H), 7.38 (d, J = 8.2 Hz, 2H), 7.55 (d, J = 8.2 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 21.0, 21.1, 22.8, 24.5, 24.6, 25.4, 32.4, 32.6, 48.4, 51.0, 62.4, 124.0 (q, J_C–F = 274.5 Hz), 125.4 (q, J_C–F = 3.7 Hz, 2C), 127.3 (2C), 129.6 (q, J_C–F = 32.7 Hz), 141.0, 169.4, 171.1; HRMS (ESI) calcd for [C₂₀H₂₇F₃N₂O₂ + Na⁺]: 407.1922, found: 407.1920.

N-Cyclohexyl-2-(N-isopropylacetamido)-2-(4-methoxyphenyl)-acetamide (2f)

Following the general procedure, the reduction of amide 1f (97 mg, 0.5 mmol) gave, after flash column chromatography on silica gel (eluent: EtOAc/hexane = 1/8), the desired product 2f (48 mg, 28%) as a white solid. Mp: 144–146 °C (solvent: MeOH). IR (film) ν_max 3294, 3063, 2924, 2852, 1651, 1618, 1512, 1447, 1369, 1307, 1252, 1181, 1032, 833 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 1.00–1.14 (m, 3H), 1.07 (d, J = 6.7 Hz, 3H), 1.23–1.39 (m, 2H), 1.37 (d, J = 6.7 Hz, 3H), 1.48–1.64 (m, 3H), 1.78–1.87 (m, 2H), 2.18 (s, 3H), 3.69–3.83 (m, 1H), 3.79 (s, 3H), 4.12 (septet, J = 6.7 Hz, 1H), 4.73 (s, 1H), 6.15 (d, J = 7.4 Hz, 1H), 6.84 (d, J = 8.6 Hz, 2H), 7.25 (d, J = 8.6 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 21.0, 21.4, 22.7, 24.6, 24.7, 25.5, 32.6 (2C), 48.3, 50.6, 55.2, 61.7, 113.9 (2C), 129.2 (3C), 159.0, 169.8, 170.6; HRMS (ESI) calcd for [C₂₀H₃₀N₂O₃ + Na⁺]: 369.2154, found: 369.2154.

N-Cyclohexyl-2-(N-isopropylacetamido)-2-(naphthalen-1-yl)acetamide (2g)

Following the general procedure, the reduction of amide 1g (107 mg, 0.5 mmol) gave, after flash column chromatography on silica gel (eluent: EtOAc/hexane = 1/15), the desired product 2g (148 mg, 81%) as a white solid. Mp: 167–168 °C (solvent: MeOH). IR (film) ν_max 3422, 3269, 3057, 2931, 2855, 1657, 1626, 1541, 1446, 1370, 1318, 1198, 1132, 1026, 891, 782 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 0.67 (d, J = 6.7 Hz, 3H), 0.75–1.01 (m, 3H), 1.15–1.26 (m, 2H), 1.37–1.55 (m, 3H), 1.46 (d, J = 6.7 Hz, 3H), 1.58–1.68 (m, 1H), 1.78–1.87 (m, 1H), 2.25 (s, 3H), 3.62–3.81 (m, 1H), 3.97–4.20 (m, 1H), 5.30 (d, J = 5.4 Hz, 1H), 5.81 (s, 1H), 7.40–7.55 (m, 3H), 7.55–7.66 (m, 1H), 7.75–7.92 (m, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 21.1 (2C), 22.9, 24.5 (2C), 25.3, 32.3 (2C), 48.4, 49.8, 58.4, 122.8, 125.4, 125.7, 126.7, 126.9, 128.9, 129.0, 131.2, 131.6, 133.6, 168.6, 170.9; HRMS (ESI) calcd for [C₂₃H₃₀N₂O₂ + Na⁺]: 389.2205, found: 389.2204.

N-Cyclohexyl-2-(N-isopropylacetamido)dodecanamide (2h)

Following the general procedure, the reduction of amide 1h (107 mg, 0.5 mmol) gave, after flash column chromatography on silica gel (eluent: EtOAc/hexane = 1/5), the desired product 2h (118 mg, 62%) as a colorless oil. IR (film) ν_max 3304, 3060, 2927, 2854, 1652, 1624, 1541, 1450, 1371, 1317, 1195, 1129 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 0.88 (t, J = 6.8 Hz, 3H), 1.18–1.36 (m, 27H), 1.53–1.70 (m, 3H), 1.78–1.87 (m, 2H), 1.96–2.03 (m, 1H), 2.08–2.15 (m, 1H), 2.16 (s, 3H), 3.62–3.88 (m, 2H), 3.98 (septet, J = 6.7 Hz, 1H), 7.75 (br s, 1H); ¹³C NMR (126 MHz, CDCl₃) δ 14.1, 20.7, 21.1, 22.6, 23.5, 24.5 (2C), 25.6, 27.0, 29.3, 29.4 (2C), 29.5 (2C), 30.0, 31.9, 32.5, 32.7, 47.6, 50.5, 61.2, 171.7, 172.3; HRMS (ESI) calcd for [C₂₃H₄₄N₂O₂ + Na⁺]: 403.3300, found: 403.3298.

N-Cyclohexyl-2-(N-isopropylacetamido)hexanamide (2i)

Following the general procedure, the reduction of amide 1i (72 mg, 0.5 mmol) gave, after flash column chromatography on silica gel (eluent: EtOAc/hexane = 1/5), the desired product 2i (113 mg, 76%) as a colorless oil. IR (film) ν_max 3299, 3057, 2932, 2859, 1656, 1538, 1448, 1369, 1317, 1196, 1135 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 0.83 (t, J = 7.3 Hz, 3H), 1.17 (d, J = 6.7 Hz, 3H), 1.19 (d, J = 6.7 Hz, 3H), 1.09–1.32 (m, 9H), 1.47–1.66 (m, 3H), 1.71–1.85 (m, 2H), 1.89–2.11 (m, 2H), 2.12 (s, 3H), 3.58–3.76 (m, 2H), 3.93 (septet, J = 6.7 Hz, 1H), 7.69 (br s, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 13.9, 20.7, 21.1, 22.5, 22.8, 23.5, 24.5 (2C), 25.6 (2C), 29.2, 29.7, 32.5, 32.7, 47.6, 171.7, 172.2; HRMS (ESI) calcd for [C₁₇H₃₂N₂O₂ + Na⁺]: 319.2361, found: 319.2360.

N-Cyclohexyl-2-(N-isopropylacetamido)-4-methylpentanamide (2j)

Following the general procedure, the reduction of amide 1j (72 mg, 0.5 mmol) gave, after flash column chromatography on silica gel (eluent: EtOAc/hexane = 1/5), the desired product 2j (110 mg, 74%) as a white solid. Mp: 102–104 °C (solvent: MeOH). IR (film) ν_max 3304, 3057, 2931, 2859, 1654, 1539, 1447, 1370, 1321, 1195, 1127 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 0.88 (d, J = 6.4 Hz, 3H), 0.91 (d, J = 6.4 Hz, 3H), 1.20 (d, J = 7.0 Hz, 3H), 1.22 (d, J = 7.0 Hz, 3H), 1.09–1.35 (m, 5H), 1.46–1.68 (m, 5H), 1.73–1.84 (m, 2H), 2.06–2.21 (m, 1H), 2.11 (s, 3H), 3.58–3.71 (m, 1H), 3.94 (m, 2H), 7.60 (br s, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 20.7, 21.2, 22.4, 23.0, 23.6, 24.4, 24.5, 25.4, 25.5, 32.5, 32.6, 39.2, 47.5, 50.3, 58.9, 171.7, 171.8; HRMS (ESI) calcd for [C₁₇H₃₂N₂O₂ + Na⁺]: 319.2361, found: 319.2358.

N,2-Dicyclohexyl-2-(N-isopropylacetamido)acetamide (2k)

Following the general procedure, the reduction of amide 1k (85 mg, 0.5 mmol) gave, after flash column chromatography on silica gel (eluent: EtOAc/hexane = 1/5), the desired product 2k (147 mg, 91%) as a white solid. Mp: 138–140 °C (solvent: MeOH). IR (film) ν_max 3286, 3054, 2929, 2853, 1657, 1540, 1445, 1363, 1329, 1192, 1034 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 0.61–0.78 (m, 1H), 1.03–1.34 (m, 15H), 1.46–1.82 (m, 10H), 2.12 (s, 3H), 2.54 (m, 1H), 3.21 (m, 1H), 3.56–3.74 (m, 1H), 3.95 (septet, J = 6.7 Hz, 1H), 8.25 (br s, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 20.6, 21.2, 23.5, 24.4 (2C), 25.6, 25.9 (2C), 26.3, 30.4, 30.8, 32.5, 32.6, 35.8, 47.4, 51.1, 67.6, 171.7, 172.0; HRMS (ESI) calcd for [C₁₉H₃₄N₂O₂ + Na⁺]: 345.2518, found: 345.2513.

2-(N-Butylacetamido)-N-cyclohexyl-2-phenylacetamide (2l)

Following the general procedure, the reduction of amide 1l (89 mg, 0.5 mmol) gave, after flash column chromatography on silica gel (eluent: EtOAc/hexane = 1/10), the desired product 2l (117 mg, 71%) as a white solid. Mp: 123–125 °C (solvent: MeOH, lit.³² mp: 123 °C). IR (film) ν_max 3298, 3064, 2930, 2857, 1634, 1544, 1451, 1417, 1369, 1300, 1194, 1134, 1042, 738, 700 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 0.73 (t, J = 7.2 Hz, 3H), 0.91–1.46 (m, 9H), 1.51–1.72 (m, 3H), 1.80–1.97 (m, 2H), 2.16 (s, 3H), 3.28 (t, J = 8.0 Hz, 2H), 3.68–3.92 (m, 1H), 5.84 (s, 1H), 5.90 (s, 1H), 7.26–7.46 (m, 5H); ¹³C NMR (100 MHz, CDCl₃) δ 13.4, 20.0, 21.7, 24.7 (2C), 25.5, 31.6, 32.7 (2C), 47.6, 48.5, 62.4, 128.2, 128.6 (2C), 129.3 (2C), 135.7, 168.9, 171.4; HRMS (ESI) calcd for [C₂₀H₃₀N₂O₂ + Na⁺]: 353.2199, found: 353.2203.

N-Cyclohexyl-2-(N-phenethylacetamido)-2-phenylacetamide (2m)

Following the general procedure, the reduction of amide 1m (113 mg, 0.5 mmol) gave, after flash column chromatography on silica gel (eluent: EtOAc/hexane = 1/10), the desired product 2m (110 mg, 58%) as a white solid. Mp: 150–152 °C (solvent: MeOH). IR (film) ν_max 3297, 3061, 3024, 2929, 2854, 1634, 1541, 1449, 1413, 1221, 1161, 1027 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 1.07–1.18 (m, 3H), 1.30–1.40 (m, 2H), 1.58–1.70 (m, 3H), 1.89–1.95 (m, 2H), 2.17–2.23 (m, 1H), 2.18 (s, 3H), 2.62–2.72 (m, 1H), 3.43–3.57 (m, 2H), 3.77–3.89 (m, 1H), 5.70 (d, J = 7.4 Hz, 1H), 5.98 (s, 1H), 6.90 (d, J = 7.4 Hz, 2H), 7.14–7.23 (m, 3H), 7.39–7.49 (m, 5H); ¹³C NMR (126 MHz, CDCl₃) δ 21.8, 24.8 (2C), 25.5, 32.8 (2C), 36.2, 48.6, 49.1, 61.8, 126.5, 128.5 (2C), 128.6 (3C), 128.9 (2C), 129.7 (2C), 135.8, 138.3, 168.8, 171.5; HRMS (ESI) calcd for [C₂₄H₃₀N₂O₂ + Na⁺]: 401.2205, found: 401.2201.

2-(N-Allylacetamido)-N-cyclohexyl-2-phenylacetamide (2n)

Following the general procedure, the reduction of amide 1n (81 mg, 0.5 mmol) gave, after flash column chromatography on silica gel (eluent: EtOAc/hexane = 1/10), the desired product 2n (88 mg, 56%) as a white solid. Mp: 134–136 °C (solvent: MeOH). IR (film) ν_max 3298, 3069, 2929, 2855, 1634, 1544, 1453, 1412, 1316, 1255, 1192, 1040 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 1.01–1.17 (m, 3H), 1.26–1.38 (m, 2H), 1.52–1.70 (m, 3H), 1.83–1.93 (m, 2H), 2.12 (s, 3H), 3.71–3.85 (m, 1H), 3.89–4.02 (m, 2H), 4.89–4.99 (m, 2H), 5.34–5.49 (m, 1H), 5.86 (d, J = 7.4 Hz, 1H), 6.07 (s, 1H), 7.28–7.38 (m, 5H); ¹³C NMR (100 MHz, CDCl₃) δ 22.0, 24.7 (2C), 25.4, 32.7 (2C), 48.5, 49.4, 61.2, 116.3, 128.3, 128.6 (2C), 129.4 (2C), 134.2, 135.6, 168.6, 172.1; HRMS (ESI) calcd for [C₁₉H₂₆N₂O₂ + Na⁺]: 337.1892, found: 337.1888.

Methyl-4-(2-(cyclohexylamino)-1-(N-isopropylacetamido)-2-oxoethyl)benzoate (2o)

Following the general procedure, the reduction of amide 1o (111 mg, 0.5 mmol) gave, after flash column chromatography on silica gel (eluent: EtOAc/hexane = 1/8), the desired product 2o (161 mg, 86%) as a colorless oil. IR (film) ν_max 3294, 3057, 2931, 2855, 1723, 1655, 1539, 1439, 1367, 1280, 1189, 1110, 1021, 969, 743 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 1.03–1.11 (m, 3H), 1.13 (d, J = 6.7 Hz, 3H) 1.25–1.33 (m, 2H), 1.35 (d, J = 6.7 Hz, 3H), 1.46–1.62 (m, 3H), 1.78–1.86 (m, 2H), 2.18 (s, 3H), 3.71–3.81 (m, 1H), 3.87 (s, 3H), 4.15 (septet, J = 6.7 Hz, 1H), 4.84 (s, 1H), 6.62 (d, J = 7.4 Hz, 1H), 7.33 (d, J = 8.4 Hz, 2H), 7.96 (d, J = 8.4 Hz, 2H); ¹³C NMR (126 MHz, CDCl₃) δ 21.0, 21.1, 22.7, 24.4, 24.5, 25.4, 32.4, 32.5, 48.2, 50.9, 52.0, 62.4, 127.1 (2C), 129.3, 129.7 (2C), 142.1, 166.5, 169.3, 171.0; HRMS (ESI) calcd for [C₂₁H₃₀N₂O₄ + Na⁺]: 397.2103, found: 397.2106.

2-(4-Cyanophenyl)-N-cyclohexyl-2-(N-isopropylacetamido)acetamide (2p)

Following the general procedure, the reduction of amide 1p (94 mg, 0.5 mmol) gave, after flash column chromatography on silica gel (eluent: EtOAc/hexane = 1/10), the desired product 2p (125 mg, 73%) as a white solid. Mp: 159–160 °C (solvent: MeOH). IR (film) ν_max 3295, 3058, 2932, 2854, 2228, 1655, 1540, 1504, 1446, 1370, 1308, 1196, 1170, 1097, 892, 831 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 1.03–1.23 (m, 3H), 1.20 (d, J = 6.7 Hz, 3H), 1.25–1.37 (m, 2H), 1.34 (d, J = 6.7 Hz, 3H), 1.48–1.64 (m, 3H), 1.77–1.89 (m, 2H), 2.18 (s, 3H), 3.70–3.83 (m, 1H), 4.18 (septet, J = 6.7 Hz, 1H), 4.84 (s, 1H), 6.94 (d, J = 7.4 Hz, 1H); 7.34 (d, J = 8.3 Hz, 2H), 7.57 (d, J = 8.3 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 20.8, 21.1, 22.7, 24.4 (2C), 25.3, 32.3, 32.5, 48.2, 51.1, 62.5, 111.2, 118.4, 127.4 (2C), 132.1 (2C), 142.2, 169.1, 171.1; HRMS (ESI) calcd for [C₂₀H₂₇N₃O₂ + Na⁺]: 364.2001, found: 364.1997.

N-Cyclohexyl-2-(N-isopropylacetamido)-2-(4-nitrophenyl)acetamide (2q)

Following the general procedure, the reduction of amide 1q (104 mg, 0.5 mmol) gave, after flash column chromatography on silica gel (eluent: EtOAc/hexane = 1/10), the desired product 2q (141 mg, 78%) as a white solid. Mp: 149–151 °C (solvent: MeOH). IR (film) ν_max 3296, 3071, 2931, 2853, 1656, 1605, 1520, 1448, 1347, 1195, 1110, 892, 854 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 1.04–1.15 (m, 3H), 1.20 (d, J = 6.7 Hz, 3H), 1.24–1.35 (m, 2H), 1.33 (d, J = 6.7 Hz, 3H), 1.46–1.62 (m, 3H), 1.76–1.86 (m, 2H), 2.17 (s, 3H), 3.69–3.81 (m, 1H), 4.18 (septet, J = 6.7 Hz, 1H), 4.86 (s, 1H), 6.99 (d, J = 7.5 Hz, 1H), 7.38 (d, J = 8.8 Hz, 2H), 8.10 (d, J = 8.8 Hz, 2H); ¹³C NMR (126 MHz, CDCl₃) δ 20.7, 21.0, 22.7, 24.3 (2C), 25.3, 32.2, 32.4, 48.2, 51.1, 62.3, 123.4 (2C), 127.4 (2C), 144.2, 146.9, 169.0, 171.2; HRMS (ESI) calcd for [C₁₉H₂₇N₃O₄ + Na⁺]: 384.1899, found: 384.1899.

2-(4-Acetylphenyl)-N-cyclohexyl-2-(N-isopropylacetamido)acetamide (2r)

Following the general procedure, the reduction of amide 1r (103 mg, 0.5 mmol) gave, after flash column chromatography on silica gel (eluent: EtOAc/hexane = 1/10), the desired product 2r (115 mg, 64%) as a colorless gummy. IR (film) ν_max 3294, 3054, 2930, 2855, 1678, 1538, 1439, 1362, 1310, 1267, 1191 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 1.02–1.18 (m, 3H), 1.16 (d, J = 6.7 Hz, 3H), 1.25–1.38 (m, 2H), 1.35 (d, J = 6.7 Hz, 3H), 1.46–1.62 (m, 3H), 1.78–1.87 (m, 2H), 2.18 (s, 3H), 2.54 (s, 3H), 3.70–3.83 (m, 1H), 4.17 (septet, J = 6.7 Hz, 1H), 4.84 (s, 1H), 6.74 (d, J = 7.3 Hz, 1H), 7.34 (d, J = 8.2 Hz, 2H), 7.87 (d, J = 8.2 Hz, 2H); ¹³C NMR (126 MHz, CDCl₃) δ 21.0, 21.1, 22.7, 24.4, 24.5, 25.4, 26.4, 32.4, 32.5, 48.2, 51.0, 62.5, 127.1 (2C), 128.4 (2C), 136.2, 142.2, 169.4, 171.0, 197.3; HRMS (ESI) calcd for [C₂₁H₃₀N₂O₃ + Na⁺]: 381.2154, found: 381.2152.

N-Cyclohexyl-2-(4-formylphenyl)-2-(N-isopropylacetamido)acetamide (2s)

Following the general procedure, the reduction of amide 1s (96 mg, 0.5 mmol) gave, after flash column chromatography on silica gel (eluent: EtOAc/hexane = 1/15), the desired product 2s (81 mg, 47%) as a colorless gummy. IR (film) ν_max 3293, 3057, 2930, 2854, 1694, 1660, 1537, 1440, 1370, 1309, 1210 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 1.06–1.22 (m, 3H), 1.20 (d, J = 6.7 Hz, 3H), 1.27–1.39 (m, 2H), 1.34 (d, J = 6.7 Hz, 3H), 1.48–1.65 (m, 3H), 1.79–1.89 (m, 2H), 2.21 (s, 3H), 3.72–3.86 (m, 1H), 4.19 (septet, J = 6.7 Hz, 1H), 4.88 (s, 1H), 6.84 (d, J = 7.3 Hz, 1H), 7.43 (d, J = 8.2 Hz, 2H), 7.82 (d, J = 8.2 Hz, 2H), 9.97 (s, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 21.0, 21.2, 22.8, 24.5 (2C), 25.4, 32.4, 32.6, 48.3, 51.1, 62.7, 127.5 (2C), 129.8 (2C), 135.5, 143.8, 169.4, 171.1, 191.5; HRMS (ESI) calcd for [C₂₀H₂₈N₂O₃ + Na⁺]: 367.1998, found: 367.1996.

Acknowledgements

The authors are grateful for financial support from the National Natural Science Foundation of China (NSFC, 21332007), Chinese Universities Scientific Fund (No. 20720150048) and the Program for Changjiang Scholars and Innovative Research Team in University (PCSIRT) of the Ministry of Education.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: ¹H NMR and ¹³C NMR spectra of the products 2a–2s. See DOI: 10.1039/c5qo00146c

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