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Article

Copper-Catalyzed N-Arylation of Amides Using (S)-N-Methylpyrrolidine-2-carboxylate as the Ligand

1
College of Chemical Engineering and Material, Heilongjiang University, Haerbin 150080, China
2
Mudanjiang Normal University, Mudanjiang 157012, China
*
Author to whom correspondence should be addressed.
Molecules 2010, 15(3), 1154-1160; https://doi.org/10.3390/molecules15031154
Submission received: 23 January 2010 / Revised: 25 February 2010 / Accepted: 2 March 2010 / Published: 2 March 2010

Abstract

:
(S)-N-methylpyrrolidine-2-carboxylate, a derivative of natural L-proline, was found to be an efficient ligand for the copper-catalyzed Goldberg-type N-arylation of amides with aryl halides under mild conditions. A variety of N-arylamides were synthesized in good to high yields.

1. Introduction

N-Arylamides are valuable compounds widely employed in the fields of organic synthesis, pharmaceutical chemistry, or biology [1,2,3]. One of the most common synthetic protocols for their preparation is the copper-catalyzed Ullmann reaction [4] and the related Goldberg reaction (copper-catalyzed N-arylation of amides) [5]. However, classic Ullmann reactions are usually conducted under harsh conditions, and therefore their applications would be restricted. In recent years, some efficient ligands [6,7,8,9] have been disclosed for copper-catalyzed N-arylation under mild conditions including diamines [10,11,12], diimines [13], amino acids [14,15], β-keto esters [16], and diols [17]. Some ligand-free Ullmann-type coupling reactions have also been reported [18,19,20,21,22]. However, it is well accepted that some reactions require 10 mol% of copper as a catalyst and long reaction times for the reaction to proceed accordingly. We now report the use of (S)-N-methylpyrrolidine-2-carboxylate (Figure 1), a derivative of natural L-proline, as the ligand of 5 mol % copper catalyst in the N-arylation of amides. Satisfactory results were obtained under mild conditions and short reaction time.
Figure 1. (S)-N-methylpyrrolidine-2-carboxylate (ligand).
Figure 1. (S)-N-methylpyrrolidine-2-carboxylate (ligand).
Molecules 15 01154 g001
Table 1. Optimization of reaction conditions for N-phenylation of 2-pyrrolidone.
Table 1. Optimization of reaction conditions for N-phenylation of 2-pyrrolidone.
Molecules 15 01154 i001
EntrySubstrateLigandBaseSolventTemperature
(°C)
Time (h)Yield
(%)
1PhILKOt-BuDMF110510
2PhILKOHDMF110513
3PhILCs2CO3DMF110560
4PhILK2CO3DMF110561
5PhILNa2CO3DMF110563
6PhILLi2CO3DMF110566
7PhILK3PO4DMF110576
8PhILK3PO4DMF110776
9PhILK3PO4DMF120575
10PhILK3PO4DMF90562
11PhI-K3PO4DMF110515
12PhILK3PO4DMSO110590
13PhILK3PO4DMSO110790
14 PhBrLK3PO4DMSO110511
15 PhClLK3PO4DMSO11053

2. Results and Discussion

The ligand (S)-N-methylpyrrolidine-2-carboxylate was synthesized according to the reported procedure [23]. Initially, we tried to seek the optimal reaction conditions for copper-catalyzed N-arylation of amides. Aryl halides and 2-pyrrolidone were chosen as the model substrates with 5 mol % of CuI as a catalyst under an argon atmosphere at 110 °C (Table 1). In the presence of (S)-N-methylpyrrolidine 2-carboxylate as a ligand and DMF as a solvent, K3PO4 was found to be the most appropriate base, 110 °C to be the most appropriate reaction temperature, and 5 hours to be the most appropriate reaction time (entries 1–10). Without using the ligand, the yield was greatly decreased (entry 11). The effect of various aryl halides and solvents was investigated (entries 7,12,14,15). The use of aryl iodides as substrate and DMSO as a solvent led to a best result for this reaction (entry 12). Based on those results, the effect of Goldberg-type N-arylations of various amides with various aryl iodides was investigated (entries 1–11, Table 2). Using 4-substituted aryl iodides led to good yields of the desired products (entries 1–4). Moreover, 2-iodotoluene and 1-iodonaphthalene also led to good yields (entries 5,6).
Table 2. Copper-catalyzed N-arylations of amides with aryl iodides.
Table 2. Copper-catalyzed N-arylations of amides with aryl iodides.
Molecules 15 01154 i002
EntryAryl iodideAmideProductsYield (%) a
1 Molecules 15 01154 i003 Molecules 15 01154 i004 Molecules 15 01154 i005b90
2 Molecules 15 01154 i006 Molecules 15 01154 i007 Molecules 15 01154 i008c89
3 Molecules 15 01154 i009 Molecules 15 01154 i010 Molecules 15 01154 i011d93
4 Molecules 15 01154 i012 Molecules 15 01154 i013 Molecules 15 01154 i014e88
5 Molecules 15 01154 i015 Molecules 15 01154 i016 Molecules 15 01154 i017f89
6 Molecules 15 01154 i018 Molecules 15 01154 i019 Molecules 15 01154 i020g85
5 Molecules 15 01154 i021 Molecules 15 01154 i022 Molecules 15 01154 i023h86
6 Molecules 15 01154 i024 Molecules 15 01154 i025 Molecules 15 01154 i026i93
7 Molecules 15 01154 i027 Molecules 15 01154 i028 Molecules 15 01154 i029j81
8 Molecules 15 01154 i030 Molecules 15 01154 i031 Molecules 15 01154 i032k79
9 Molecules 15 01154 i033 Molecules 15 01154 i034 Molecules 15 01154 i035l75
10 Molecules 15 01154 i036 Molecules 15 01154 i037 Molecules 15 01154 i038m76 (10 b)
11 Molecules 15 01154 i039 Molecules 15 01154 i040 Molecules 15 01154 i041n80 (11 b)
Note: a Isolated yield, b bisphenylated yield.
The N-phenylation of various amides gave the corresponding products with moderate to good yields (entries 7–11). In the reaction of acetamide, bisphenylation product was obtained accompanying the corresponding product (entries 10–11, Table 2).

3. Experimental

3.1. General

All starting compounds were used as received from commercial sources without further purification. Petroleum ether (PE) used had the boiling range 60–90 °C. Melting points were determined on a XRC-1 micromelting point apparatus and are uncorrected. Column chromatography was carried out on silica gel (200–300 mesh, Qingdao Haiyang Chemical Co., Ltd.). NMR spectra were recorded at 300 MHz (1H) and 75 MHz (13C) in CDCl3 on a Bruker Avance 300 spectrometer with TMS as internal standard. MS spectra measurements were carried out on a Finnigan LCQDECA mass spectrometer (ESI-MS) and a BioTOF-Q mass spectrometer (HR-ESI-MS).

3.2. General procedure for copper-catalyzed N-arylations of amides with aryl iodides

Under an atmosphere of Ar, aryl iodide (12 mmol) was added to the mixture of amide (10 mmol), K3PO4 (10 mmol), ligand (1 mmol), and CuI (0.5 mmol) in DMSO (10 mL) at r.t. The mixture was stirred at 110 °C. After 5 h, the mixture was cooled to r.t. diluted with EtOAc, and filtered through Celite, eluting with additional EtOAc. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel chromatography using a mixture of hexane and EtOAc as eluent. All prepared compounds a-n are known and identified by 1H- and 13C-NMR and MS.
1-Phenylpyrrolidin-2-one (a): mp 68–69 °C. 1H-NMR: δ = 2.12 (m, 2H), 2.45 (t, J = 7.5 Hz, 2H), 3.31 (t, J = 7.1 Hz, 2H), 7.00 (d, J = 8.0 Hz, 2H), 7.21 (m, 1H), 7.46 (m, 2H). 13C NMR: δ = 18.1, 32.7, 49.1, 122.1, 125.3, 131.2, 142.5, 175.3. MS (EI): m/z = 161 (100) [M+]. HRMS: m/z calcd for C10H11NO: 161.2005; found: 161.2013.
1-(4-Acetylphenyl)pyrrolidin-2-one (b): mp 91–93 °C. 1H-NMR: δ = 2.16 (m, 2H), 2.38 (t, J = 6.5 Hz, 2H), 2.56 (s, 3H), 3.45 (t, J = 6.8 Hz, 2H), 7.62 (d, J = 7.6 Hz, 2H), 8.10 (d, J = 8.7 Hz, 2H). 13C- NMR: δ = 17.1, 30.3, 32.5, 48.6, 122.3, 129.8, 133.1, 146.6, 175.2, 197.6. MS (EI): m/z = 203 (100) [M+]. HRMS: m/z calcd for C12H13NO2: 203.2372; found: 203.2365.
1-(4-Trifluoromethylphenyl)pyrrolidin-2-one (c): mp 86–88 °C. 1H-NMR: δ = 2.15 (m, 2H), 2.58 (t, J = 7.3 Hz, 2H), 3.32 (t, J = 7.6 Hz, 2H), 7.00 (d, J = 7.2 Hz, 2H), 7.65 (d, J = 8.6 Hz, 2H). 13C-NMR: δ = 18.5, 33.6, 48.9, 122.1, 123.5, 125.0, 127.6, 147.5, 175.8. MS (EI): m/z = 229 (100) [M+]. HRMS: m/z calcd for C11H10F3NO: 229.1984; found: 229.1976.
1-(4-Methylphenyl)pyrrolidin-2-one (d): mp 73.5–75.1 °C. 1H-NMR: δ = 2.13 (m, 2H), 2.38 (s, 3H), 2.56 (t, J = 7.0 Hz, 2H), 3.21 (t, J = 6.3 Hz, 2H), 6.89 (d, J = 7.5 Hz, 2H), 7.12 (d, J = 8.5 Hz, 2H). 13C-NMR: δ = 17.6, 24.9, 33.1, 49.2, 122.1, 130.5, 134.7, 139.2, 175.8. MS (EI): m/z = 175 (100) [M+]. HRMS: m/z calcd for C11H13NO: 175.2271; found: 175.2262.
1-(4-Methoxyphenyl)pyrrolidin-2-one (e): mp 89.5–91.0 °C. 1H-NMR: δ = 2.15 (m, 2H), 2.55 (t, J = 7.6 Hz, 2H), 3.23 (t, J = 7.3 Hz, 2H), 3.71 (s, 3H), 3.806.80 (d, J = 7.6 Hz, 2H), 7.05 (d, J = 8.2 Hz, 2H). 13C-NMR: δ = 17.5, 32.6, 48.7, 56.2, 114.8, 122.1, 135.6, 156.9, 175.2. MS (EI): m/z = 191 (100) [M+]. HRMS: m/z calcd for C11H13NO2: 191.2265; found: 191.2261.
1-(4-Bromophenyl)pyrrolidin-2-one (f): mp 99.5–101.0 °C. 1H-NMR: δ = 2.20 (m, 2H), 2.50 (t, J = 7.2 Hz, 2H), 3.34 (t, J = 7.4 Hz, 2H), 6.83 (d, J = 7.5 Hz, 2H), 7.41 (d, J = 8.1 Hz, 2H). 13C-NMR: δ = 17.6, 33.2, 48.0, 118.1, 124.1, 132.4, 142.9, 175.0. MS (EI): m/z = 239 (100) [M+]. HRMS: m/z calcd for C10H10BrNO: 238.9912; found: 238, 9908.
Methyl 4-(2-oxopyrrolidin-1-yl)benzoate (g): mp 80.5–82.0 °C. 1H-NMR: δ = 2.21 (m, 2H), 2.61 (t, J = 7.0 Hz, 2H), 3.38 (t, J = 7.5 Hz, 2H), 3.91 (s, 3H), 6.83 (d, J = 7.6 Hz, 2H), 7.76 (d, J = 8.0 Hz, 2H). 13C-NMR: δ = 17.0, 33.2, 49.2, 52.3, 122.8, 126.2, 131.1, 147.2, 167.2, 175.3. MS (EI): m/z = 219 (100) [M+]. HRMS: m/z calcd for C12H13NO2: 219.0915; found: 219.0906.
1-(2-Methylphenyl)pyrrolidin-2-one (h): mp 74–75.2 °C. 1H-NMR: δ = 2.12 (m, 2H), 2.31 (t, J = 7.6 Hz, 2H), 2.38 (s, 3H), 3.42 (t, J = 7.4 Hz, 2H), 6.90 (d, J = 7.2 Hz, 1H), 7.00-7.21 (m, 3H). 13C-NMR: δ =14.8, 17.3, 33.5, 48.0, 122.3, 124.5, 126.3, 131.7, 134.0, 139.7, 175.2. MS (EI): m/z = 175 (100) [M+]. HRMS: m/z calcd for C11H13NO: 175.2271; found: 175.2265.
1-(Naphthalen-1-yl)pyrrolidin-2-one (i): mp 87.5–89.0 °C. 1H-NMR: δ = 2.05 (m, 2H), 2.34 (t, J = 7.5 Hz, 2H), 2.71 (t, J = 7.6 Hz, 2H), 6.50 (d, J = 6.8 Hz, 1H), 7.10–7.66 (m, 6H). 13C-NMR: δ =17.6, 33.5, 49.6, 110.2, 119.3, 121.6, 124.0, 124.9, 126.1, 126.9, 129.0, 135.1, 143.2, 176.2. MS (EI): m/z = 211 (100) [M+]. HRMS: m/z calcd for C14H13NO: 211.2592; found: 211.2590.
1-Phenylpiperidin-2-one (j): mp 71.3–72.1 °C. 1H-NMR: δ = 1.47 (m, 2H), 1.72 (m, 2H), 2.67 (t, J = 7.6 Hz, 2H), 3.36 (t, J = 7.2 Hz, 2H), 7.12 (d, J = 7.4 Hz, 2H), 7.22–7.40 (m, 3H). 13C-NMR: δ = 23.1, 27.1, 34.2, 49.1, 122.3, 123.8, 129.6, 142.5, 170.2. MS (EI): m/z = 175 (100) [M+]. HRMS: m/z calcd for C11H13NO: 175.2271; found: 175.2272.
N-Methyl-N-phenylacetamide (k): mp 100–101 °C. 1H-NMR: δ = 2.36 (s, 3H), 2.83 (s, 3H) 7.11 (d, J = 7.3 Hz, 2H), 7.26–7.38 (m, 3H). 13C-NMR: δ =21.2, 33.0, 122.6, 124.8, 129.8, 142.5, 171.3. MS (EI): m/z = 149 (100) [M+]. HRMS: m/z calcd for C9H11NO: 149.1898; found: 149.1893.
N, N-Diphenylacetamide (l): mp 101–103 °C. 1H-NMR: δ = 2.43 (s, 3H), 7.01–7.32 (m, 6H) 7.69 (d, J = 7.2 Hz, 4H). 13C-NMR: δ =21.2, 118.8, 119.6, 130.1, 141.3, 173.4. MS (EI): m/z = 211 (100) [M+]. HRMS: m/z calcd for C14H13NO: 211.2592; found: 211.2597.
N-Phenylacetamide (m): mp 155–156 °C. 1H-NMR: δ = 2.33 (s, 3H), 7.11–7.32 (m, 3H) 7.66 (d, J = 7.4 Hz, 4H), 9.12 (s, 1H). 13C-NMR: δ =23.1, 122.3, 124.7, 130.2, 140.0, 168.2. MS (EI): m/z = 135 (100) [M+]. HRMS: m/z calcd for C8H9NO: 135.1632; found: 135.1621.
N-Phenylbenzamide (n): mp 163–164.5 °C. 1H-NMR: δ = 6.92–7.30 (m, 3H), 7.40–7.58 (m, 3H), 7.70 (d, J = 7.2 Hz, 2H), 7.91 (d, J = 7.4 Hz, 2H). 9.01 (s, 1H). 13C-NMR: δ = 120.5, 123.2, 127.5, 129.1, 132.8, 134.6, 135.2, 166.5. MS (EI): m/z = 197 (100) [M+]. HRMS: m/z calcd for C13H11NO: 197.08646; found: 197.0841.

4. Conclusions

In summary, we have developed a simple and highly efficient ligand, (S)-N-methylpyrrolidine-2-carboxylate, that can promote the copper-catalyzed Goldberg-type N-arylation of amides with aryl iodides. Further work is in progress to examine its catalytic activity in other copper-catalyzed organic transformations.

Acknowledgments

This work was supported by grants from Youth Fund of Education Department of Heilongjiang Province (11531279), Youth Fund of Science and Technology Department of Heilongjiang Province (QC07C65), and Technological Innovation Fund of Harbin Municipal Science and Technology Bureau (2008RFQXS106).

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Sample Availability: Samples of the compounds are available from the authors.

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MDPI and ACS Style

Wang, C.; Liu, L.; Wang, W.; Ma, D.-S.; Zhang, H. Copper-Catalyzed N-Arylation of Amides Using (S)-N-Methylpyrrolidine-2-carboxylate as the Ligand. Molecules 2010, 15, 1154-1160. https://doi.org/10.3390/molecules15031154

AMA Style

Wang C, Liu L, Wang W, Ma D-S, Zhang H. Copper-Catalyzed N-Arylation of Amides Using (S)-N-Methylpyrrolidine-2-carboxylate as the Ligand. Molecules. 2010; 15(3):1154-1160. https://doi.org/10.3390/molecules15031154

Chicago/Turabian Style

Wang, Chaoyu, Lijuan Liu, Wei Wang, Dong-Sheng Ma, and Hua Zhang. 2010. "Copper-Catalyzed N-Arylation of Amides Using (S)-N-Methylpyrrolidine-2-carboxylate as the Ligand" Molecules 15, no. 3: 1154-1160. https://doi.org/10.3390/molecules15031154

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