New Stable Cu(I) Catalyst Supported on Weakly Acidic ... - MDPI

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New Stable Cu(I) Catalyst Supported on Weakly Acidic Polyacrylate Resin for Green C-N Coupling: Synthesis of N-(Pyridin-4-yl)benzene Amines and N,N-Bis(pyridine-4-yl)benzene Amines Nitin Kore and Pavel Pazdera * Centre for Syntheses at Sustainable Conditions and their Management, Department of Chemistry, Faculty of Science, Masaryk University, Kamenice 5, CZ-62500 Brno, Czech Republic; [email protected] * Correspondence: [email protected]; Tel.: +420-608-209-346 Academic Editor: Julio A. Seijas Vázquez Received: 19 October 2016; Accepted: 5 December 2016; Published: 22 December 2016

Abstract: A method for preparation of a new stable Cu(I) catalyst supported on weakly acidic polyacrylate resin without additional stabilizing ligands is described. A simple and efficient methodology for Ullmann Cu(I) catalyzed C-N cross coupling reactions using this original catalyst is reported. Coupling reactions of 4-chloropyridinium chloride with anilines containing electron donating (EDG) or electron withdrawing (EWG) groups, naphthalen-2-amine and piperazine, respectively, are successfully demonstrated. Keywords: polymer solid support; supported Cu(I) catalyst; C-N coupling; recyclable green catalyst

1. Introduction Synthetic applications of copper(I)-catalyzed post-Ullmann-type coupling syntheses have been well known for decades, however, they have remained relatively limited because of the required harsh reaction conditions involving high temperatures, highly polar solvents, use of further ligands and use of stoichiometric amounts of copper(I) reagents. Several studies were reported in the literature for post Ullmann-type methods, e.g., the N-arylation of anilines [1,2], imidazoles [3], amides [4], nitrogen containing heterocycles [5] and hydrazides [6] as well. However, all above reported C-N coupling reactions are homogeneously catalyzed and carried out in the presence of ligands, which are necessary for stabilization of both possible oxidation states of the copper intermediates, i.e., Cu(I) and Cu(III). In some articles, uses of cuprous oxide [7,8], copper(I) halide salts [9], CuO nanoparticles [10,11] and silica supported copper(I) complex [12] for N-arylation reaction as heterogeneous catalysts are described. However, these methodologies involve high temperatures as well as highly polar solvents (DMF). Arylaminopyridine moiety in molecules is useful in biological and pharmaceutical science [13]. Syntheses of compounds with aminopyridine moiety are mainly reported as C-N cross coupling reactions of amino pyridine with activated aryl halide [14,15] catalyzed by Pd(0) complexes in polar solvent such as DMF, 1,4-dioxane etc. C-N coupling of aryl amines with 4-chloropyridin-1-ium chloride using Pd(0) catalyst was reported by Keddie et al. [16]. No reports are available on C-N cross coupling of aryl amines with 4-chloropyridine using the Ullmann copper catalysis yet. Cation exchange resins are easily available and used for different purposes in industry as well as in laboratory. Use of cation exchange resins as a support for deposition of charged metal ion and metal complexes for different catalytic reactions were studied [17–20]. Modified cation exchange resin is easily separable from reaction mixture compared to other solid supports such as silica, alumina,

Molecules 2017, 22, 2; doi:10.3390/molecules22010002

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Molecules 2017, 22, 2

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carbon, zeolite, etc. due to its larger size and, simultaneously, the resin, unlike hard supports, does not rub against the surface of reaction vessels. The goal of our work is to demonstrate catalytic application of bare Cu(I) ion supported on weakly acidic polyacrylate resin at mild reaction conditions. Herein, we report the method for preparation of this supported catalyst as a catalyst for C-N cross coupling reactions of different amines with 4-chloropyridine in the absence of ligands for stabilization of possible oxidation states of the copper intermediates. 2. Results and Discussion The selective reduction methods of Cu(II) to Cu(I) may be carried out by action of iodide ion, cyanide ion [21], or using sodium ascorbate [22]. Few articles demonstrate the use of hydroxyl amine as a reducing agent for reduction of copper(II) complex [23], reduction of copper(II) sulfate [24,25] and to reduce Cu(II) ion [26] to corresponding Cu(I). In this work, we used hydroxyl ammonium chloride successfully to reduce polymer supported Cu(II) ion in ammine complex form to Cu(I). We found that obtained supported Cu(I) catalyst is very stable against oxidation by air oxygen due to stabilization of Cu(I) ions probably by flexible coordination in the field of carboxylate functional groups present in the weakly acidic macroporous cation exchange resin. We decided to try the coupling reaction of 4-methoxyaniline with 4-chloropyridine catalyzed by title supported Cu(I) catalyst as a model reaction, because of nucleophilic properties of 4-methoxyaniline and, moreover, their coupling product prepared by Pd(0) catalyzed reaction with result of good yield was reported previously [16] (Table 1). Table 1. Comparison of different catalytic conditions for C-N coupling of 4-methoxyaniline with 4-chloropyridine. Sr. No.

Catalyst

Product Yield (%)

TON

1 2 3

Cu(I) ions supported on a weekly acidic cation-exchanger resin Copper(I) iodide No catalyst

64 8 0

23.6 2.9 0

Reaction conditions: A mixture of 4-methoxyaniline (1.20 g, 9.74 mmol), 4-chloropyridin-1-ium chloride (1.21 g, 8.12 mmol), anhydrous potassium carbonate (3.45 g, 25 mmol) and supported Cu(I) catalyst (100 mg, 0.22 mmol) or copper(I) iodide (50.0 mg, 0.26 mmol) or no catalyst was refluxed in isopropyl alcohol (40 mL) for 24 h in open atmosphere conditions.

We were pleased to find that the reaction occurred to afford N-4-pyridyl(p-methoxyphenyl)amine in 64% yield in presence of Cu(I) ions supported on weakly acidic cation-exchanger resin as a catalyst. However, the reaction using CuI as a catalyst affords only 8% of product and in the case of process without catalyst there was no reaction at all at the same reaction conditions. We suppose that the presence of sufficient amount of carboxylate moieties on resin stabilizes Cu(I) catalyst, hence it shows much better activity than only CuI. To investigate the further scope of the procedure, we attempted to carry out the reaction with a broader spectrum of different aromatic amines (Scheme 1). The temperature of boiling isopropyl alcohol as well as the presence of potassium carbonate or hydrogen carbonate as a base in the reaction mixture evoked decomposition of 4-chloropyridine after 24 h during the course of synthesis, hence duration of all reactions was kept for 24 h. We successfully recycled the title Cu(I) catalyst twenty times for C-N coupling of 4-methoxyaniline with 4-chloropyridine without losing any activity (see Supplementary Materials). TON (turnover number) was calculated as a ratio of mole of 4-chloropyridin-1-ium chloride converted to product and mole of Cu present in catalyst.

alcohol as well as the presence of potassium carbonate or hydrogen carbonate as a base in the reaction mixture evoked decomposition of 4-chloropyridine after 24 h during the course of synthesis, hence duration of all reactions was kept for 24 h. We successfully recycled the title Cu(I) catalyst twenty times for C-N coupling of 4-methoxyaniline with 4-chloropyridine without losing any activity (see Supplementary Materials). TON (turnover number) was calculated as a ratio of mole Molecules 2017, 22, 2 3 of of 11 4-chloropyridin-1-ium chloride converted to product and mole of Cu present in catalyst.

Scheme 1. C-N Scheme 1. C-N coupling coupling reaction reaction with with 4-chloropyridin-1-ium 4-chloropyridin-1-ium chloride chloride with with substituted substituted aniline. aniline. R R11–H/EDG/EWG; –H/EDG/EWG;R2R–H/Pyridine. –H/Pyridine. 2

The C-N coupling of 4-chloropyridine with anilines containing electron donating substituents, i.e., 4-N,N-diethylbenzene-1,4-diamine, 4-N,N-dimethylbenzene-1,4-diamine, 4-ethoxy-, Molecules 2017, 22, 2 3 of 10 Molecules 2017, 22, 2 3 of 10 or 4-methoxyanilinem afforded products with the only one amino group hydrogen atom Molecules 2017, 22, 2 3 of 10 replaced in Molecules 2017, 22, 2 3 of 10 Molecules 2017, 22, 2 3 of 10 Molecules 2017, 22, 2 3 of 10 The C-N coupling of 4-chloropyridine with anilines containing electron donating The C-N coupling of 4-chloropyridine with anilines containing electron donating 64%–80%Molecules yield (Table entries 1–2, 4–5). Molecules 22, 2 3 of 10 2017, 22, 2 2,2017, 3 of 10 The C-N ofcoupling of 4-chloropyridine withcontaining anilines containing electron donating The C-N coupling 4-chloropyridine with anilines electron donating Molecules 2017, 22, 2 4-N,N-diethylbenzene-1,4-diamine, 3 of 10 Molecules 2017, 22, 2 4-N,N-diethylbenzene-1,4-diamine, 3 of 10 substituents, i.e., 4-N,N-dimethylbenzene-1,4-diamine, 4-ethoxy-, substituents, i.e., 4-N,N-dimethylbenzene-1,4-diamine, 4-ethoxy-, The C-N of 4-chloropyridine with anilines containing electron donating The2017, C-N 4-chloropyridine with anilines containing electron 4-ethoxy-, donating Molecules 22, 2 coupling 3 of 10 Molecules 2017, 22, 2ofcoupling 3 of 10 substituents, i.e., 4-N,N-diethylbenzene-1,4-diamine, 4-N,N-dimethylbenzene-1,4-diamine, 4-ethoxy-, substituents, i.e., 4-N,N-diethylbenzene-1,4-diamine, 4-N,N-dimethylbenzene-1,4-diamine, or 4-methoxyanilinem afforded products with the only one amino group hydrogen atom replaced or 4-methoxyanilinem afforded products with the only oneanilines amino group hydrogen atom replaced in The C-N coupling of 4-chloropyridine with anilines containing electron donating The C-N coupling of 4-chloropyridine with containing electron donating Molecules 2017, 22, 2 3 of in 10 Molecules 2017, 22, 2 3 of 10 substituents, i.e.,ofcoupling 4-N,N-diethylbenzene-1,4-diamine, 4-N,N-dimethylbenzene-1,4-diamine, 4-ethoxy-, substituents, i.e., 4-N,N-diethylbenzene-1,4-diamine, 4-N,N-dimethylbenzene-1,4-diamine, 4-ethoxy-, or 4-methoxyanilinem afforded products with the only one amino group hydrogen atom replaced The C-N of 4-chloropyridine with anilines containing electron donating or 4-methoxyanilinem afforded products with the only one amino group hydrogen atom replaced in The C-N coupling 4-chloropyridine with anilines containing electron donating Molecules 2017, 22, 2 3 of in 10 Molecules 2017, 22, 2 3 of 10 64%–80% yield (Table 2, entries 1–2, 4–5). 64%–80% yield (Table 2, entries 1–2, 4–5). substituents, i.e.,ofcoupling 4-N,N-diethylbenzene-1,4-diamine, 4-N,N-dimethylbenzene-1,4-diamine, 4-ethoxy-, substituents, i.e., 4-N,N-diethylbenzene-1,4-diamine, 4-N,N-dimethylbenzene-1,4-diamine, 4-ethoxy-, The C-N coupling 4-chloropyridine with anilines containing electron donating The C-N of 4-chloropyridine with anilines containing electron donating or 4-methoxyanilinem afforded products with the only one amino group hydrogen atom replaced in or 4-methoxyanilinem afforded products with the only one amino group hydrogen atom replaced in Molecules 2017, 22, 2 3 of 10 Molecules 2017, 22, 2 3 of 10 64%–80% yield (Table 2,4–5). entries 1–2, 4–5). 64%–80% yield (Table 2, entries 1–2, substituents, i.e.,of 4-N,N-diethylbenzene-1,4-diamine, 4-N,N-dimethylbenzene-1,4-diamine, 4-ethoxy-, substituents, i.e., 4-N,N-diethylbenzene-1,4-diamine, 4-N,N-dimethylbenzene-1,4-diamine, 4-ethoxy-, The C-N coupling of 4-chloropyridine with anilines containing electron donating The2017, C-N coupling 4-chloropyridine with containing electron donating or afforded products with the only one amino group hydrogen or 4-methoxyanilinem afforded products with the4–5). only oneanilines amino group hydrogen atom replaced Molecules 22, 24-methoxyanilinem 3 atom of in 10 replaced Molecules 2017, 22, 2(Table 3 of in 10 substituents, i.e., 4-N,N-diethylbenzene-1,4-diamine, 4-N,N-dimethylbenzene-1,4-diamine, 4-ethoxy-, substituents, i.e., 4-N,N-diethylbenzene-1,4-diamine, 4-N,N-dimethylbenzene-1,4-diamine, 4-ethoxy-, 64%–80% yield 2, entries 1–2,

Table 2. Comparison of pure product yields for different aromatic amines in C-N coupling reaction with 64%–80% 4-chloropyridin-1-ium chloride yield (Table 2, entries 1–2, 4–5).in the presence of potassium carbonate as a base. The C-N of 4-chloropyridine with anilines containing electron donating The C-N coupling ofcoupling 4-chloropyridine with anilines containing electron donating or 4-methoxyanilinem afforded products with the only one amino group hydrogen atom replaced in or 4-methoxyanilinem afforded products with thedifferent only one amino group hydrogen atom replaced in reaction Table 2of Comparison of pure product yields for different aromatic in C-N coupling Tableyield 2 Comparison pure product yields for aromatic amines in C-Namines coupling reaction substituents, i.e., 4-N,N-diethylbenzene-1,4-diamine, 4-N,N-dimethylbenzene-1,4-diamine, 4-ethoxy-, substituents, i.e., 4-N,N-diethylbenzene-1,4-diamine, 4-N,N-dimethylbenzene-1,4-diamine, 4-ethoxy-, 64%–80% yield (Table 2, entries 1–2, 4–5). 64%–80% (Table 2, entries 1–2, 4–5). The C-N coupling of 4-chloropyridine with anilines containing electron donating The C-N coupling of 4-chloropyridine with anilines containing electron donating or 4-methoxyanilinem afforded products with thedifferent only one amino group hydrogen atom replaced in reaction or 4-methoxyanilinem afforded products with the only one amino group hydrogen atom replaced in Table 2of Comparison of product yields for different aromatic amines in coupling Table4-chloropyridin-1-ium 2 Comparison pure product yields for aromatic amines in coupling reaction substituents, i.e., 4-N,N-diethylbenzene-1,4-diamine, 4-ethoxy-, substituents, i.e., 4-N,N-diethylbenzene-1,4-diamine, 4-N,N-dimethylbenzene-1,4-diamine, 4-ethoxy-, 64%–80% yield (Table 2, entries 1–2, 4–5). 64%–80% yield (Table 2, entries 1–2, 4–5). with 4-chloropyridin-1-ium chloride in the presence of4-N,N-dimethylbenzene-1,4-diamine, potassium asC-N areplaced base. with chloride inpure the presence of potassium carbonate asC-N acarbonate base. The C-N coupling of 4-chloropyridine with anilines containing electron donating The C-N coupling of 4-chloropyridine with anilines containing electron donating or 4-methoxyanilinem afforded products with the only one amino group hydrogen atom replaced in or 4-methoxyanilinem afforded products with the only one amino group hydrogen atom in Table 2of Comparison of product for different aromatic amines inasC-N coupling reaction Table 2 Comparison pure product yields for different aromatic amines inasC-N coupling reaction substituents, i.e., 4-N,N-diethylbenzene-1,4-diamine, 4-N,N-dimethylbenzene-1,4-diamine, 4-ethoxy-, substituents, i.e., 4-N,N-diethylbenzene-1,4-diamine, 4-N,N-dimethylbenzene-1,4-diamine, 4-ethoxy-, 64%–80% yield (Table 2, entries 1–2,2, 4–5). 64%–80% yield (Table entries 1–2, 4–5). with 4-chloropyridin-1-ium chloride inyields the presence of potassium areplaced base. with 4-chloropyridin-1-ium chloride inpure the presence of potassium carbonate acarbonate base. or 4-methoxyanilinem afforded products with the only one amino group hydrogen atom replaced in or 4-methoxyanilinem afforded products with the only one amino group hydrogen atom in Entry Amine Product Yield (%) Table 2of Comparison of pure product yields for different aromatic amines inasC-N coupling reaction Table4-chloropyridin-1-ium 2 Comparison pure product yields for different aromatic amines inasC-N coupling reaction substituents, i.e., 4-N,N-diethylbenzene-1,4-diamine, 4-N,N-dimethylbenzene-1,4-diamine, 4-ethoxy-, substituents, i.e., 4-N,N-diethylbenzene-1,4-diamine, 4-N,N-dimethylbenzene-1,4-diamine, 4-ethoxy-, 64%–80% yield (Table 2, entries 1–2, 4–5). 64%–80% yield (Table 2, entries 1–2, 4–5). with 4-chloropyridin-1-ium chloride in the presence of potassium carbonate a base. with chloride in the presence of potassium carbonate a base. or 4-methoxyanilinem afforded products with the only one amino group hydrogen atom replaced or 4-methoxyanilinem afforded products with thedifferent only one amino group hydrogen atom replaced in reaction Entry Amine Product Yield (%) TON in Entry Product Yield (%) TON Table 2Amine Comparison of pure product yields for different aromatic amines in C-N coupling Table 2 Comparison of pure product yields for aromatic amines in C-N coupling reaction 64%–80% yield (Table entries 1–2, 4–5). 64%–80% yield (Table 2, entries 1–2,2, 4–5). with 4-chloropyridin-1-ium chloride inyields presence of potassium asC-N areplaced base. with 4-chloropyridin-1-ium chloride inpure the presence ofthe potassium carbonate asC-N acarbonate base. or 4-methoxyanilinem afforded products with thedifferent only one amino group hydrogen atom in reaction 4-methoxyanilinem afforded products with the only one amino group hydrogen atom replaced Entry Amine Product Yield (%) TON in Entry Product Yield (%) TON Table 2 or Comparison of pure product for aromatic in coupling Table 2Amine Comparison of product for different aromatic amines in coupling 64%–80% yield (Table entries 1–2, 4–5). 64%–80% yield (Table 2, entries 1–2,2, 4–5). with 4-chloropyridin-1-ium inofthe presence ofamines potassium asreaction a TON base. with 4-chloropyridin-1-ium chloride inyields thechloride presence potassium carbonate as acarbonate base. Entry Amine Product Yield (%) reaction TON Entry Amine Product Yield (%) Table 2 Comparison of pure product yields for different aromatic amines in C-N coupling Table 2 Comparison of pure product yields for different aromatic amines in C-N coupling reaction 64%–80% yield (Table 2, entries 1–2, 4–5). 64%–80% yield (Table 2, entries 1–2, 4–5). with 4-chloropyridin-1-ium chloride in thechloride presenceinofthe potassium carbonate as acarbonate base. (%)as a TON with 4-chloropyridin-1-ium presence of potassium base. Entry Amine Product Yield (%) TON Entry Amine Product Yield Table 2of Comparison of pure product for different aromatic amines inasC-N coupling reaction Table 2 Comparison purechloride product yields for different aromatic inasC-N coupling reaction with 4-chloropyridin-1-ium inyields presence ofamines potassium a TON base. with 4-chloropyridin-1-ium inpure thechloride presence ofthe potassium carbonate acarbonate base. Entry Amine Product Yield TON Entry Product Yield Table 2Amine Comparison ofin product for different aromatic amines inas C-N coupling Table 2 Comparison of purechloride product yields for different aromatic inas C-N coupling reaction 1 4-chloropyridin-1-ium 80 (%) reaction 29.5 1 4-chloropyridin-1-ium 80(%) 29.5 1 with inyields the presence ofamines potassium a Yield base. with thechloride presence of potassium carbonate acarbonate base. Entry Amine Product Yield (%) TON Entry Amine Product (%) 80 TON Table 2 Comparison of pure product yields for different aromatic amines in C-N coupling reaction Table 2 Comparison of pure product yields for different aromatic amines in C-N coupling 1 29.5 1 80 29.5 with 4-chloropyridin-1-ium the presence carbonate of potassium base.80 (%) reaction with 4-chloropyridin-1-ium chloride in thechloride presenceinof potassium as acarbonate base. (%)as a TON Entry Amine Product Yield TON Entry Amine Product Yield 1 80 29.5 1 80 29.5 with 4-chloropyridin-1-ium chloride in the presence of potassium carbonate as a base. with 4-chloropyridin-1-ium chloride in the presence of potassium carbonate as a base. EntryAmine Amine Product Yield (%) Yield (%) TON Entry Product TON 1 80 29.5 1 80 29.5 Entry Amine Product Yield Yield (%) TON Entry Product TON 1 Amine 29.5 1 80 (%) 29.580(%) Entry Product TON Entry Amine Product Yield TON 1 80(%) Yield 29.580 1 Amine 29.5 1 29.5 1 80 29.580 2 78 28.7 2 78 28.7 1 29.5 1 80 29.580 78 28.7 78 28.780 12 12 80 29.5 2 7829.5 80 29.580 12 29.5 78 28.7 21 78 28.7 2 28.7 2 78 28.778 2 28.7 2 78 28.778 2 78 28.778 2 28.7 2 78 28.7 23 78 28.7 22 8.1 22 8.178 23 28.7 2 78 28.7 22 8.1 22 8.178 23 28.7 23 78 28.7 22 8.1 32 22 8.178 3 2228.7 78 28.7 23 3 8.1 3 22 8.122 3 8.1 3 22 8.122 3 22 8.122 3 8.1 22 8.1 34 22 8.1 43 25 68 2568 34 8.1 34 22 8.1 68 25 68 2522 3 22 8.1 3 22 8.1 4 25 4 68 2568 3 22 8.1 3 22 8.1 4 68 25 4 68 25 4 68 4 25 4 68 2568 4 68 2568 4 25 5 64 23.6 5 64 23.6 4 25 4 68 2568 64 23.6 64 23.6 45 25 45 68 2568 64 23.6 54 64 23.6 45 25 68 2568 64 23.6 54 64 23.6 68 2568 45 25 5 5 64 23.664 5 6423.6 5 64 23.6 5 64 23.6 6 4.4 6 12 4.412 56 23.6 56 64 23.6 12 4.4 12 4.464 56 23.6 64 23.6 12 4.4 65 12 4.464 56 64 23.6 64 23.6 12 4.4 655 12 4.4 64 23.6 56 23.6 12 4.4 6 12 4.464 76 14.7 76 40 14.7 12 4.440 12 4.4 6 12 40 14.7 40 14.7 67 4.4 67 12 4.412 40 14.7 76 40 14.7 67 4.4 12 4.412 67 4.4 40 14.7 76 40 14.7 12 4.412 40 14.7 76 40 14.7 12 4.412 67 4.4 40 14.746 40 14.7 87 16.9 87 46 16.9 78 78 40 14.7 7 4014.7 46 16.9 46 16.940 78 14.7 40 14.740 46 16.9 87 46 16.9 78 14.7 40 14.740 46 16.9 877 46 16.9 40 14.7 7 40 14.7 8 16.9 8 46 16.946 8 46 16.946 8 16.9 98 17.3 47 17.347 46 16.9 89 46 16.9 9 47 17.3 9 47 17.3 8 8 46 16.946 8 4616.9 47 17.3 98 47 17.3 89 16.9 46 16.946 9 47 17.3 98 47 17.3 46 16.946 8 16.9 9 17.3 9 47 17.347 9 47 17.347 9 17.3 10 45 16.6 10 45 16.6 9 17.3 9 47 17.347 10 45 16.6 10 45 16.6 9 47 17.3 9 47 17.3 10 45 16.6 10 45 16.6 9 17.3 9 47 17.347 9 47 10 45 16.6 10 45 16.6 9 47 17.347 9 17.3 10 16.6 10 45 16.645 10 45 16.645 10 16.6 11 49 18 11 49 18 10 16.6 10 45 16.645 11 49 18 11 49 1845 10 16.6 10 45 16.6 11 49 18 11 49 1845 10 16.6 10 45 16.6 11 49 18 11 49 18 10 45 16.645 10 10 4516.6 11 18 11 49 1849 11 49 1849 11 18 11 18 11 49 1849 11 18 11 49 1849 11 18 11 49 1849 11 49 1849 11 18

TON

29.5

28.7

8.1

25

23.6

4.4

14.7

16.9

17.3

16.6

7

7

40

14.740

14.7

8

8

46

16.946

16.9

Molecules 2017, 22, 2 9

4 of 11 9

47

17.347

45

16.645

49

1849

17.3

Table 2. Cont. Entry 11

10

Molecules 2017, 22, 2

11

10

Amine

11

Molecules 22 Molecules 2017, 22, 2 Molecules 2017, 2017, 22, 22, Molecules 2017, 2017, 22, 22, 22 Molecules Molecules 2017, 22, 2 Molecules 2017, 22, 2 Molecules 2017, 22, 2 12 Molecules 2017, 2017, 22, 22, Molecules 22 Molecules 2017, 22, 2 Molecules 2017, 22, 2 12 Molecules12 2017, 22, 2 12 Molecules12 2017, 22, 2 12 Molecules12 2017, 22, 2

12

12

13

12 12 12 12 12 12

13 13

13 13 13 13 13 13 13 13 13 13

26

9.526 26 26 9.526 26 9.526 26 26 26 24 26 24 24 24 30.924 24 30.924 24 30.924 24 30 30.930 30 30 30 30 30 30 30 30 10 10 10 10 27.3 10 27.310 10 27.310 10 10 32 27.332 32 32 32 32 32 32 3132 32 3142 42 42 3142 42 3142 42 42 42 9 42 99 32.109 9 32.109 9 32.109 9 39 9 39 32.10 39 39 39 39 39 39 39 6 39 66 20 6 6 20 6 6 20 6 6 24 6 24 2024 24 24 24 24 24 24 24

26 26 24 24 24 30 30 30 30

14

10

14

10

14 14

15 15 15

15

15

16

16 16

32 32 32

42 42 42 9 9 9

16 16

32

42 15 15 15 15 15 15 15 15 15 15

16 16 16 16 16 16 16 16 16 16

9 39 39 39 39 6 6 6

17 17 17

17

17

17 17 17 17 17 17 17 17 17 17

4918

4 of 10

9.5

10

14 14 14 14 14 14 14 14 14 14

4 of 10

26

10

14

16.6

Yield (%)

44 of of 10 10

24

13 13

Product

6 24 24 24 24

of 10 10 44 of

9.5 269.5

9.5 9.5 9.5 9.5 9.5 9.5 9.5 249.5

TON 18

4 of 10 of 10 10 44 of 4 of 10 4 of 10 4 of 10 4 of 10 4 of 10 4 of 10 4 of 10

9.5

30.9

30.9 30.9 30.9 30.9 30.9 30.9 3030.9 30.9 30.9 30.9

10

27.3

27.3 27.3 27.3 27.3 27.3 27.3 27.3 27.3 3227.3 27.3

31 31 31 31 31 4231 31 31 31 31

32.10 932.10 32.10

32.10 32.10 32.10 32.10 32.10 32.10 32.10

31

32.10

39

20 20 20 20 6 20 20 20 20 20 20

24

20

Molecules 2017, 22, 2

5 of 11

Molecules 2017, 22, 2

5 of 10

Table 2. Cont.

Molecules 2017, 22, 2 Entry Amine Molecules 2017, 22, 2 Molecules 2017, 22, 2

Product

6

Molecules 2017, 22, 2 Molecules 2017, 22, 2 Molecules 2017, 22, 2 Molecules 2017, 22, 2

18

6

18

18 18

18 18 18 18 18

39 6

39 39

5 of 10 Yield (%) TON 5 of 10

5 of 10

65 of 10 31 6 6 6 6 31 39 39 3139 39 39

6

5 of 10 5 of 10 5 of 10

31

31 31 31 31 3931

42 19 42

19

19 19

19 19 19 19 19

4 42

32.4 42 42 42 42 32.442

4232.4

32.4 32.4 32.4 32.4

32.4

32.4 4 4 20 24 4 4 4 4 4 Reaction conditions: g, 20 A mixture of aryl amine (9.74 mmol), 4-chloropyridin-1-ium chloride (1.21 65 24 20mmol), anhydrous 65 20 65 24 8.12 potassium carbonate (3.45 g, 25 mmol) and supported Cu(I) catalyst (10024 mg, 20 65 24 0.22 mmol) was refluxed in isopropyl alcohol (40 mL) for 24 h in open atmosphere conditions. 20 65 24 Reaction conditions: A mixture of aryl amine (9.74 mmol), 4-chloropyridin-1-ium chloride (1.21 g, 20 conditions: 65 2465 20 A mixture of aryl amine (9.74 mmol), 4-chloropyridin-1-ium chloride 6524g, 24 20 Reaction (1.21 g, Reaction conditions: A mixture of aryl amine(3.45 (9.74g, mmol), 4-chloropyridin-1-ium chloride (1.21 8.12 mmol), anhydrous potassium carbonate 25 aniline, mmol) and supported Cu(I) catalyst mg, The synthetic process with sterically hindered o-substituted e.g., 2,5-dimethoxyand(100 Reaction conditions: Acarbonate mixture of aryl amine (9.74 4-chloropyridin-1-ium chloride (1.21mg, g, 8.12 mmol), anhydrous potassium (3.45 g,alcohol 25 mmol) and supported Cu(I) catalyst (100 conditions. mg, 8.12 mmol) mmol), anhydrous potassium carbonate (3.45 g, mmol), 25 mmol) and supported Cu(I) catalyst (100 0.22 was refluxed in isopropyl (40 mL) for 24 h in open atmosphere Reaction conditions: A mixture of (9.74 mmol), 4-chloropyridin-1-ium (1.21mg, g, 2,4-dimethylaniline, underwent replacement of aryl one amine amine hydrogen atom in 22% and 12%chloride yield,(100 8.12 mmol), anhydrous potassium carbonate g, 25for mmol) and supported Cu(I) catalyst 0.22 mmol) was refluxed in isopropyl alcohol (40 mL) for 24(3.45 h inmL) open atmosphere conditions. 0.22 mmol) was refluxed in isopropyl alcohol (40 24 h in open atmosphere conditions. Reaction conditions: A mixture of Aaryl amine (9.74 mmol), 4-chloropyridin-1-ium chloride (1.21 g, Reaction conditions: mixture of aryl amine (9.74 4-chloropyridin-1-ium chloride (1.21mg, g, 8.12 mmol), anhydrous potassium (3.45 g, mmol), 25for mmol) and supported Cu(I) catalyst (100 respectively. Low0.22 yields of the reactions becarbonate inflicted by steric hindrance of atmosphere o-substitutes in the mmol) was refluxed inmay isopropyl alcohol (40 4-chloropyridin-1-ium mL) 24 h in open conditions. Reaction conditions: A mixture of aryl amine (9.74 mmol), chloride (1.21 g, 8.12 mmol), 8.12 mmol), anhydrous potassium carbonate (3.45 g,alcohol 25 mmol) and supported Cu(I) catalyst (100 mg, 8.12 mmol) mmol), anhydrous potassium carbonate (3.45 g, 25 mmol) and supported Cu(I) catalyst (100 mg, and The synthetic process with sterically hindered o-substituted aniline, e.g., 2,5-dimethoxy0.22 was refluxed in isopropyl (40 mL) for 24 h in open atmosphere conditions. molecule (Table 2,The entries 3,with 6). process anhydrous potassium carbonate (3.45alcohol g,isopropyl 25replacement mmol) and supported Cu(I) catalyst (100 mg, 0.22 mmol) The synthetic process sterically hindered o-substituted aniline, e.g., 2,5-dimethoxyand synthetic with sterically o-substituted aniline, e.g., 2,5-dimethoxyand was 0.22 mmol) was refluxed in isopropyl (40 mL) forhindered 24of h in open atmosphere 0.22 mmol) was refluxed in alcohol (40 mL) for 24 hhydrogen in openconditions. atmosphere conditions. 2,4-dimethylaniline, underwent one amine atom in 22% and 12% yield, The reaction with slightly deactivated substituted aniline, 4-chloro-, 4-bromo-, 4-iodo-, The synthetic process with sterically hindered o-substituted aniline, e.g., 2,5-dimethoxyand refluxed in isopropyl alcohol (40 mL) for 24 h in open atmosphere conditions. 2,4-dimethylaniline, underwent replacement of one amine hydrogen atom in 22% and 12% yield, 2,4-dimethylaniline, underwent replacement of one amine hydrogen atom in 22% and 12% yield, respectively. Low yields of with the reactions may be inflicted byreplacement steric aniline, hindrance of2,5-dimethoxyo-substitutes inand the The ethyl synthetic process sterically hindered o-substituted 4-fluoroaniline, and 4-aminobenzoate, underwent reaction with ofe.g., one amine 2,4-dimethylaniline, underwent replacement of amine atom inof22% and 12% in yield, respectively. Low yields of the reactions may be inflicted by steric hindrance o-substitutes inand the respectively. Low of3,with the reactions may beone inflicted byhydrogen steric hindrance o-substitutes the The synthetic process with sterically hindered o-substituted aniline, e.g.,ofaniline, 2,5-dimethoxyThe synthetic process sterically hindered o-substituted 2,5-dimethoxyand (Table 2, yields entries 6). 2,4-dimethylaniline, underwent replacement of one amine hydrogen atome.g., inof22% and 12% in yield, hydrogen(Table in molecule 26%–49% yield (Table 2, entries 8–12). respectively. Low yields of the reactions may be inflicted by steric hindrance o-substitutes the molecule 2, entries 3, 6). molecule (Table 2, entries 3, 6). replacement 2,4-dimethylaniline, underwent replacement of one amine hydrogen atom in 22% and 12% yield, 2,4-dimethylaniline, underwent of one amine hydrogen atom in 22% and 12% yield, The reaction with slightly deactivated substituted aniline, 4-chloro-, 4-bromo-, 4-iodo-, respectively. Low of3,the reactions may be inflicted by stericofhindrance of o-substitutes in the Our observation of formation of C-N coupling product under replacement only one hydrogen molecule (Table 2, yields entries 6). The reaction with slightly deactivated substituted aniline, 4-chloro-, 4-bromo-, The synthetic process with sterically hindered o-substituted aniline, e.g., and The reaction with slightly deactivated 4-chloro-, 4-bromo-, respectively. Low yields of the reactions may be inflicted steric hindrance o-substitutes in the respectively. Low of the reactions may by besubstituted inflicted byaniline, stericofwith hindrance of4-iodo-, o-substitutes in the 4-fluoroaniline, and ethyl underwent reaction replacement of 2,5-dimethoxyone4-iodo-, amine molecule (Table 2, yields entries 3,4-aminobenzoate, 6). atom of aniline amino group in high yield in theunderwent case of aniline consisting electron donating group and The reaction with slightly deactivated substituted aniline, 4-chloro-, 4-bromo-, 4-fluoroaniline, and ethyl 4-aminobenzoate, reaction with replacement of one amine 4-fluoroaniline, and ethyl 4-aminobenzoate, underwent reaction with replacement of one4-iodo-, amine molecule (Table 2, entries 3, 6). molecule (Table 2, entries 3, 6). hydrogen in 26%–49% yield (Table 2, entries 8–12). 2,4-dimethylaniline, underwent replacement of one amine hydrogen atom in 22% and 12% yield, The reaction with slightly deactivated substituted aniline, 4-chloro-, 4-bromo-, 4-iodo-, formation of C-N coupling product with replacement of the8–12). only hydrogen of aniline inreplacement comparatively andwith ethyl 4-aminobenzoate, underwent reaction with of one4-iodo-, amine hydrogen in 4-fluoroaniline, 26%–49% yield (Table 2, entries 8–12). hydrogen in 26%–49% yield (Table 2, entries The reaction with slightly substituted aniline, 4-chloro-, 4-bromo-, 4-iodo-, The reaction slightly deactivated substituted aniline, 4-chloro-, 4-bromo-, Our observation ofdeactivated formation of C-N coupling product under replacement of only one hydrogen 4-fluoroaniline, and ethyl 4-aminobenzoate, underwent reaction with replacement of one amine low yield concerning aniline consisting slightly deactivating group is similar to all previously reported hydrogen information 26%–49% yield (Table 2,C-N entries 8–12). respectively. Low yields of the reactions may be inflicted by steric hindrance of o-substitutes in the Our observation of of C-N coupling product under replacement of only one hydrogen Our observation of formation of coupling product under replacement of only one hydrogen 4-fluoroaniline, and ethyl 4-aminobenzoate, underwent reaction with replacement of one amine 4-fluoroaniline, and ethyl 4-aminobenzoate, underwent reaction with replacement of one amine atom of aniline amino group in high2,yield in the case of aniline consisting electron donating group and hydrogen in 26%–49% yield (Table entries 8–12). articles [6,10,15]. Our observation of formation of C-N coupling product under replacement of only one hydrogen atom of aniline amino group in high yield in the case of aniline consisting electron donating group and atom of aniline amino group in high yield in the case of aniline consisting electron donating group and in formation 26%–49% yield (Table 2, entries 8–12). hydrogen in 26%–49% yield (Table 2,C-N entries 8–12). product molecule hydrogen (Table 2, entries 3, 6). of C-N coupling product with replacement of the only hydrogen of aniline in comparatively Our observation of formation of coupling under replacement of only one hydrogen The reaction with aniline substituted by awith strong electron withdrawing group, of aniline amino group in high in the caseproduct of aniline consisting group and formation of atom C-Nyield coupling product with replacement of the only hydrogen of aniline inelectron comparatively formation offormation C-N coupling product replacement of the only hydrogen of2,4-dichloro, in one comparatively Our observation of of C-N coupling product under replacement ofsimilar only one hydrogen Our observation of formation ofyield C-N coupling under replacement ofdonating only hydrogen low concerning aniline consisting slightly group is toaniline all previously reported atom of4-cyano, aniline amino group in high yield in thedeactivating case of aniline consisting electron donating group and 4-trifluoromethyl, 2-cyano, 3-nitroand 4-nitroaniline, ended up in formation of novel The low reaction with slightly deactivated substituted aniline, 4-chloro-, 4-bromo-, 4-iodo-, formation of C-N coupling product with replacement of the only hydrogen oftoaniline in comparatively concerning aniline consisting slightly deactivating group is similar to all previously reported low yield concerning aniline consisting slightly deactivating group is similar all previously reported atomyield of aniline amino group in high yield in the case of aniline consisting electron donating group and atom of aniline amino group in high yield in the case of aniline consisting electron donating group and articles [6,10,15]. formation of C-Namines coupling product withslightly replacement ofyield the only hydrogen oftoaniline in comparatively N,N-bis(pyridin-4-yl)benzene as a major product in 24%–42% and N-(pyridin-4-yl)benzene low yield concerning aniline consisting deactivating group is similar all previously reported articles [6,10,15]. articles [6,10,15]. formation and of low C-Nyield coupling product with replacement of the hydrogen of hydrogen aniline in comparatively formation of C-N coupling product withslightly replacement of the only oftoaniline in comparatively 4-fluoroaniline, ethyl 4-aminobenzoate, underwent reaction with replacement of one amine The reaction with aniline substituted byonly a2, strong electron withdrawing group, 2,4-dichloro, concerning aniline consisting deactivating group is similar all previously reported amines thearticles second minor product in 6%–9% yield. (Table entries 13–14, 16–19). [6,10,15]. Theasreaction with aniline substituted by a strong electron withdrawing group, 2,4-dichloro, The reaction with aniline substituted by a strong electron withdrawing group, 2,4-dichloro, low yield concerning aniline consisting slightly deactivating group is similar to all previously low yield concerning aniline consisting slightly deactivating group is similar to in allreported previously reported 4-trifluoromethyl, 4-cyano, 2-cyano, 3-nitroand 4-nitroaniline, ended up formation of novel articles [6,10,15]. hydrogen4-trifluoromethyl, in 26%–49% yield (Table 2, entries 8–12). The reaction with 2,5-dichloroaniline gave selectively the corresponding N,N-bis(pyridin-4The reaction with aniline substituted byand a strong electron 4-cyano, 2-cyano, 3-nitroand 4-nitroaniline, ended up inwithdrawing formation novel2,4-dichloro, 4-trifluoromethyl, 4-cyano, 2-cyano, 4-nitroaniline, ended up N-(pyridin-4-yl)benzene inofgroup, formation of novel articles [6,10,15]. articles [6,10,15]. N,N-bis(pyridin-4-yl)benzene amines as3-nitroa major product in electron 24%–42% yield and The reaction with aniline substituted byand a strong withdrawing 2,4-dichloro, yl)benzene amine only. 4-trifluoromethyl, 4-cyano, 2-cyano, 3-nitro4-nitroaniline, ended up in group, formation of novel N,N-bis(pyridin-4-yl)benzene amines as aC-N major product inby 24%–42% yield and N-(pyridin-4-yl)benzene Our observation of formation of coupling product under replacement of only one hydrogen N,N-bis(pyridin-4-yl)benzene amines as a6%–9% major product in electron 24%–42% yield and N-(pyridin-4-yl)benzene The reaction with aniline substituted by a strong electron withdrawing group, 2,4-dichloro, The reaction with aniline substituted a strong withdrawing group, 2,4-dichloro, amines as the second minor product in yield. (Table 2, entries 13–14, 16–19). 4-trifluoromethyl, 4-cyano, 2-cyano, 3-nitro4-nitroaniline, ended up inyield; formation of novel Theasreaction with naphthalene-2-amine (Table entryand 20) was carried out with aand high on amines as a2, major product in 24%–42% yield N-(pyridin-4-yl)benzene amines theN,N-bis(pyridin-4-yl)benzene second product in 6%–9% yield. (Table 2, entries 13–14, 16–19). amines asminor the second minor product in3-nitro6%–9% yield. (Table 2,up entries 13–14, 4-trifluoromethyl, 4-cyano, 2-cyano, 3-nitroand 4-nitroaniline, ended in formation novel donating 4-trifluoromethyl, 4-cyano, 2-cyano, and 4-nitroaniline, ended up16–19). inofformation of novel group and The reaction with 2,5-dichloroaniline gave selectively the corresponding N,N-bis(pyridin-4N,N-bis(pyridin-4-yl)benzene amines as a major product in 24%–42% yield and N-(pyridin-4-yl)benzene atom of aniline amino group in high yield in the case of aniline consisting electron the other hand, the reaction with naphthalene-1-amine gave trace amount of expected product, which we amines asreaction the second minor product in yield. (Table 2,the entries 13–14, The reaction with 2,5-dichloroaniline gave selectively the corresponding N,N-bis(pyridin-4The with 2,5-dichloroaniline selectively corresponding N,N-bis(pyridin-4N,N-bis(pyridin-4-yl)benzene amines as a major product ingave 24%–42% yield and N-(pyridin-4-yl)benzene N,N-bis(pyridin-4-yl)benzene amines as a6%–9% major product in 24%–42% yield and 16–19). N-(pyridin-4-yl)benzene yl)benzene amine only. amines asreaction the second minor product 6%–9% yield. (Table 2, entries 13–14, 16–19). were not able to purify. C-N cross coupling gave in two types ofof products, i.e., N-(pyridin-4-yl)benzene The with 2,5-dichloroaniline gave selectively the corresponding formationyl)benzene of C-N coupling product with replacement the only hydrogen ofN,N-bis(pyridin-4aniline in comparatively amine only. yl)benzene amine only. amines as the second minor product in 6%–9% yield. (Table 2, entries 13–14, 16–19). amines asreaction the second minor product in 6%–9% yield. (Table 2, entries 13–14, 16–19). The with naphthalene-2-amine (Table 2, entry 20) was carried out with a1). high yield; on reaction with 2,5-dichloroaniline gaveon selectively the corresponding N,N-bis(pyridin-4amines and/or N,N-bis(pyridine-4-yl)benzene amines2,depends electronic effect on aniline (Figure yl)benzene amine only. The reaction with naphthalene-2-amine (Table entry 20) was carried out with a high yield; on The reaction with naphthalene-2-amine (Table 2, entry 20) was carried out with a high yield; on reaction with 2,5-dichloroaniline gave selectively the corresponding N,N-bis(pyridin-4reaction with 2,5-dichloroaniline gave selectively the corresponding N,N-bis(pyridin-4low yield concerning aniline consisting slightly deactivating group is ofsimilar all previously reported the other hand, the only. reaction with naphthalene-1-amine gave trace amount expectedto product, which we yl)benzene amine The reaction with naphthalene-2-amine (Table 2,gave entry was carried outwhich with awe highwhich yield; we on the other hand, the reaction with naphthalene-1-amine gavegave tracetwo amount of20) expected product, the other hand, thepurify. reaction with naphthalene-1-amine trace amount ofi.e., expected product, yl)benzene amine only. yl)benzene amine only. were not able to C-N cross coupling types of products, N-(pyridin-4-yl)benzene The reaction with naphthalene-2-amine (Table 2, entry 20) was carried out with a high yield; on articles [6,10,15]. the other hand, the reaction with naphthalene-1-amine gave trace amount of expected product, which we wereThe not reaction ableamines to purify. C-N cross coupling gave two types of two products, i.e., N-(pyridin-4-yl)benzene were not able to purify. C-N cross coupling gave types of products, i.e., N-(pyridin-4-yl)benzene with naphthalene-2-amine (Table 2, entry 20) was carried out with high yield; The reaction with naphthalene-2-amine (Table 2,depends entry 20) was carried out with aon high(Figure yield; we on and/or N,N-bis(pyridine-4-yl)benzene amines on electronic effect onproduct, aniline 1). the other hand, thepurify. reaction with naphthalene-1-amine gave trace amount ofai.e., expected which were not able with to C-N cross coupling two types products, N-(pyridin-4-yl)benzene and/or N,N-bis(pyridine-4-yl)benzene amines electronic effect on aniline (Figure 1). group, amines and/or N,N-bis(pyridine-4-yl)benzene amines depends on electronic effect onproduct, aniline (Figure 1).2,4-dichloro, the other hand, the reaction naphthalene-1-amine gave traceon amount ofof expected product, which we the other hand, thepurify. reaction with naphthalene-1-amine gave trace amount ofi.e., expected which we The amines reaction with aniline substituted bydepends a gave strong electron withdrawing were not able to C-N cross coupling gave two types of products, N-(pyridin-4-yl)benzene and/or N,N-bis(pyridine-4-yl)benzene amines depends onproducts, electronici.e., effect on aniline (Figure 1). were not ableamines to purify. C-N cross coupling gave two types oftwo products, i.e., N-(pyridin-4-yl)benzene were not able to purify. C-N cross coupling gave types of N-(pyridin-4-yl)benzene amines and/or N,N-bis(pyridine-4-yl)benzene amines depends on electronic effect on aniline (Figure 1). 4-trifluoromethyl, 4-cyano, 2-cyano, 3-nitroandamines 4-nitroaniline, ended up in formation of novel amines and/or N,N-bis(pyridine-4-yl)benzene amines depends on electronic effect on aniline (Figure 1). (Figure 1). amines and/or N,N-bis(pyridine-4-yl)benzene depends on electronic effect on aniline 4 65

N,N-bis(pyridin-4-yl)benzene amines as a major product in 24%–42% yield and N-(pyridin-4-yl) benzene amines as the second minor product in 6%–9% yield. (Table 2, entries 13–14, 16–19). The reaction with 2,5-dichloroaniline gave selectively the corresponding N,N-bis(pyridin-4-yl) benzene amine only. The reaction with naphthalene-2-amine (Table 2, entry 20) was carried out with a high yield; on the other hand, the reaction with naphthalene-1-amine gave trace amount of expected product, which we were not able to purify. C-N cross coupling gave two types of products, i.e., N-(pyridin-4-yl) benzene amines and/or N,N-bis(pyridine-4-yl)benzene amines depends on electronic effect on aniline (Figure 1).

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Figure 1. Comparison Comparisonofofyields yields for for different different aromatic aromatic amines amines in in C-N C-N coupling coupling reaction reaction with with Figure 4-chloropyridine in in the the presence of K22CO CO33as asaabase. base. 4-chloropyridine Figure 1. Comparison of yields for different aromatic amines in C-N coupling reaction with in the presence K2CO3 as apiperazine base. In 4-chloropyridine the case of coupling reactionofbetween and 4-chloropyridinium chloride, a molar

In the case of coupling reaction between piperazine and 4-chloropyridinium chloride, a molar excess piperazine excess of of piperazine as as aa base base and and isopropyl isopropyl alcohol alcohol as as aa solvent solvent were were used. used. Only Only formation formation of of the the In the case of coupling reaction between piperazine and 4-chloropyridinium chloride, a molar 1-(pyridin-4-yl)piperazine in very good yield was observed. If the reaction was carried out under reflux 1-(pyridin-4-yl)piperazine in very yieldalcohol was observed. If the reaction was formation carried out excess of piperazine as a base andgood isopropyl as a solvent were used. Only ofunder the in methanol or in ethanol, 4-methoxyor 4-ethoxypyridine was formed due to competing reaction in reflux in methanol or in ethanol, 4-methoxyor 4-ethoxypyridine was formed due to competing 1-(pyridin-4-yl)piperazine in very good yield was observed. If the reaction was carried out under reflux yield 22%in and 18%, respectively. When using isopropyl alcohol, the above-mentioned competitive C-O reaction yield 22% and 18%, respectively. When using isopropyl the above-mentioned in methanol or in ethanol, 4-methoxyor 4-ethoxypyridine was formedalcohol, due to competing reaction in coupling reaction did not proceed at all apparently because of the presence of the bulky isopropyl competitive C-O18%, coupling reaction did using not proceed atalcohol, all apparently because of the presence of the yield 22% and respectively. When isopropyl the above-mentioned competitive C-O group and the low acidity of hydroxyl group. On the other hand, the application of potassium bulky isopropyl group and the low acidity of hydroxyl group. On the other hand, the application coupling reaction did not proceed at all apparently because of the presence of the bulky isopropyl of hydroxide, carbonate hydrogen as On a base asastemperature of boiling potassium hydroxide, carbonate or carbonate hydrogen carbonate as awell base wellapplication as temperature of solvent boiling group and the low or acidity of hydroxyl group. the as other hand, the of potassium evoked decomposition of 4-chloropyridine in the course of synthesis. solvent evoked decomposition of 4-chloropyridine the course hydroxide, carbonate or hydrogen carbonate as ainbase as well of assynthesis. temperature of boiling solvent To thethe chemistry of theofcoupling process, wesynthesis. decided accomplish same reaction evoked decomposition ofchemistry 4-chloropyridine course of To understand understand thein the coupling process, weto decided to the accomplish the using KHCO 3 as a weaker base than potassium carbonate. In the presence of KHCO 3 as a base, To understand the chemistry of the coupling process, we decided to accomplish the same reaction same reaction using KHCO3 as a weaker base than potassium carbonate. In the presence of 4-(trifluoromethyl)aniline as well as 2-aminobenzonitrile selectively corresponding using3 KHCO 3 as a4-(trifluoromethyl)aniline weaker base than potassium In the presence of KHCO 3N-(pyridin-4asselectively a base, KHCO as a base, as carbonate. wellyielded as 2-aminobenzonitrile yielded yl)benzene amines as the only product, while, in the cases of 2-nitroaniline, 2,4-dichloroaniline, 4-(trifluoromethyl)aniline as well as 2-aminobenzonitrile yielded selectively corresponding N-(pyridin-4-yl)benzene amines as the only product, while,corresponding in the cases ofN-(pyridin-42-nitroaniline, 4-aminobenzonitrile, formation ofinN-(pyridin-4-yl)benzene as a major product yl)benzene aminesand as 4-nitroaniline, the only product, while, the cases formation of 2-nitroaniline, 2,4-dichloroaniline, 2,4-dichloroaniline, 4-aminobenzonitrile, and 4-nitroaniline, ofamines N-(pyridin-4-yl)benzene 4-aminobenzonitrile, and 4-nitroaniline, formation of N-(pyridin-4-yl)benzene amines as a major(Figure product together with N,N-bis(pyridin-4-yl)benzeneamines as a secondary product was observed 2). amines as a major product together with N,N-bis(pyridin-4-yl)benzeneamines as a secondary product together with N,N-bis(pyridin-4-yl)benzeneamines as a secondary product was observed (Figure 2). was observed (Figure 2).

Figure 2. 2. Comparison yields for different aromatic amines amines in in C-N C-Ncoupling couplingreaction reactionwith with Figure 2. Comparison in C-N coupling reaction with Figure Comparisonofof ofyields yieldsfor for different different aromatic aromatic amines 4-chloropyridine in the presence of KHCO as a base. 3 4-chloropyridine in the presence of KHCO 3 as a base. 4-chloropyridine in the presence of KHCO3 as a base.

understand structural behaviorofof4-chloropyridine 4-chloropyridine derivative, derivative, we reaction To To understand structural behavior weattempted attemptedtotocarry carryout out reaction of 4-methoxyaniline with 4-chloro-1-methylpyridinium iodide iodide and of 4-methoxyaniline with 4-chloro-1-methylpyridinium and 4-chloro-3,5-dimethylpyridine. 4-chloro-3,5-dimethylpyridine.

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To understand structural behavior of 4-chloropyridine derivative, we attempted to carry out reaction of 4-methoxyaniline with 4-chloro-1-methylpyridinium iodide and 4-chloro3,5-dimethylpyridine. There was no reaction between 4-methoxyaniline and 4-chloro-3,5-dimethylpyridine observed. This can be explained by big sterical hindrance among two methyl groups and a nearby chlorine atom. This steric hindrance can be unfavorable to oxidative addition step (Table 3, entry 2). MoleculesMolecules 2017, 22, 2017, 2 7 of 10 7 of 10 22, 2 MoleculesMolecules 2017, 22, 2017, 2 10 7 of 10 22, 2 4-Chloro-1-methylpyridinium iodide underwent reaction with 4-methoxyaniline7 ofunder replacement of MoleculesMolecules 2017, 22, 2017, 2 7 of 10 7 of 10 22, 2 There was no reaction between 4-methoxyaniline and 4-chloro-3,5-dimethylpyridine observed. There was no reaction between 4-methoxyaniline and 4-chloro-3,5-dimethylpyridine observed. one hydrogen atom ofno amino group with 80% yield (Table 3, entry 3). Theobserved. presence of quaternized reaction between 4-methoxyaniline and 4-chloro-3,5-dimethylpyridine There was no reaction between 4-methoxyaniline and 4-chloro-3,5-dimethylpyridine observed. This There can bewas explained by reaction big sterical hindrance among two methyl groupsgroups and a nearby chlorine This can bewas explained by big sterical hindrance among two methyl and aobserved. nearby chlorine There was no reaction between 4-methoxyaniline and 4-chloro-3,5-dimethylpyridine There no between 4-methoxyaniline and 4-chloro-3,5-dimethylpyridine observed. This can be explained by big sterical hindrance among two methyl groups and a nearby chlorine This can be explained by big sterical hindrance among two methyl groups and a nearby chlorine pyridine nitrogen in 4-chloro-1-methylpyridinium iodide activates chlorine atom for exchange, hence atom. This steric hindrance canby be unfavorable to oxidative addition step (Table 3, entry 4-Chloroatom. This steric hindrance cansterical be unfavorable to oxidative addition step (Table 3,2). entry 2). 4-ChloroThis can besteric explained by big sterical hindrance among two methyl groups and a nearby chlorine This can be explained hindrance among two methyl groups and a 4-Chloronearby chlorine atom. This hindrance can bebig unfavorable to oxidative addition step (Table 3, entry 2). atom. This steric hindrance can be unfavorable to4-methoxyaniline oxidative addition step (Table 3,replacement entry 2).one 4-Chloro1-methylpyridinium iodide underwent reaction with under replacement of 1-methylpyridinium iodide underwent reaction with 4-methoxyaniline under of one it shows better activity than 4-chloropyridine. atom. This steric can be unfavorable to oxidative addition step (Table entry3,replacement 2). 4-Chloroatom. Thishindrance steric hindrance can bereaction unfavorable oxidative addition step 3, (Table entry 4-Chloro1-methylpyridinium iodide underwent withto4-methoxyaniline under replacement of2).one 1-methylpyridinium iodide underwent reaction with 4-methoxyaniline under of one hydrogen atom ofatom amino with 80% yield (Table 3, entry The 3). presence of quaternized pyridine hydrogen of group amino group with 80% yield (Table 3,3).4-methoxyaniline entry Theunder presence of quaternized pyridine 1-methylpyridinium iodide underwent reaction with 4-methoxyaniline replacement of one 1-methylpyridinium iodide underwent reaction with3, under replacement of one hydrogen of amino with 80% yield (Table 3, entry 3).entry The presence offor quaternized pyridine hydrogen atom of group amino group with 80% yield (Table 3). The presence ofhence quaternized pyridine nitrogen inatom 4-chloro-1-methylpyridinium iodide activates chlorine atom for exchange, ithence shows nitrogen inatom 4-chloro-1-methylpyridinium iodide activates chlorine atom exchange, it shows hydrogen atom of amino group with 80% yield (Table 3, entry 3). The presence of quaternized pyridine hydrogen of amino group with 80% yield (Table 3, entry 3). The presence of quaternized pyridine nitrogen in 4-chloro-1-methylpyridinium iodide activates chlorine atom for exchange, hence it shows nitrogen in 4-chloro-1-methylpyridinium iodide activates chlorine atom for exchange, hence it shows Comparison ofthan yields for selected 4-chloropyridine derivatives in C-N coupling Table 3.better activity than 4-chloropyridine. better activity 4-chloropyridine. nitrogen in 4-chloro-1-methylpyridinium iodide activates chlorine atom for exchange, hence ithence shows nitrogen in 4-chloro-1-methylpyridinium iodide activates chlorine atom for exchange, it shows better activity than 4-chloropyridine. better activity than 4-chloropyridine. with 4-methoxyaniline. better activity than 4-chloropyridine. better activity than 4-chloropyridine.

Entry

Table 3.Table Comparison of yieldsoffor selected 4-chloropyridine derivatives in C-N coupling reactionreaction with with 3. Comparison yields for selected 4-chloropyridine derivatives in C-N coupling Table 3.Table Comparison of yieldsoffor selected 4-chloropyridine derivatives in C-N coupling reactionreaction with with 3. Comparison yields for selected 4-chloropyridine derivatives in C-N coupling 4-methoxyaniline. 4-methoxyaniline. Table 3.Table Comparison of yieldsoffor selected 4-chloropyridine derivatives in C-N coupling reactionreaction with with 3. Comparison yields for selected 4-chloropyridine derivatives in C-N coupling 4-methoxyaniline. 4-methoxyaniline. 4-Chloropyridine Derivative Product Yield (mol %) 4-methoxyaniline. 4-methoxyaniline. Entry 4-Chloropyridine Derivative ProductProduct Yield (mol %)(molTON Entry 4-Chloropyridine Derivative Yield %) TON

Entry Entry 4-Chloropyridine Derivative 4-Chloropyridine Derivative Entry Entry 4-Chloropyridine Derivative 4-Chloropyridine Derivative

1

2

3

ProductProduct ProductProduct

reaction

TON

Yield (mol %)(molTON Yield %) TON Yield (mol Yield%)(molTON %) TON

1 1 1

1 1 1

64 64 64

64 64 64

2 2 2

2 2 2

0 0 0

0 0 0

3 3 3

3 3 3

80 80 80

80 80 80

6423.6

23.6 23.6

0

00

0

29.5 29.5

8029.5

23.6 23.6 23.6

0 0 0

29.5 29.5 29.5

23.6

0

29.5

ReactionReaction conditions: A mixture of the of corresponding 4-chloropyridine derivative (8.12 mmol), conditions: A mixture the corresponding 4-chloropyridine derivative (8.12 mmol), Reaction conditions: Ammol), mixture of the corresponding 4-chloropyridine (8.12 Reaction conditions: mixture of the potassium corresponding derivative (8.12 4-methoxyaniline (9.74 potassium carbonate (3.454-chloropyridine g, 25 mmol) 100 mg (0.22 mmol) 4-methoxyaniline (9.74Aanhydrous mmol), anhydrous carbonate (3.45 g, derivative 25and mmol) and 100 mmol), mg (0.22mmol), mmol) Reaction conditions: A mixture of the corresponding 4-chloropyridine derivative (8.12 mmol), Reaction conditions: A mixture of the corresponding 4-chloropyridine derivative (8.12 4-methoxyaniline (9.74supported mmol), anhydrous potassium carbonate (3.45 g, 25 mmol) mg mmol) (9.74 mmol), anhydrous potassium carbonate (3.45 g, 25and mmol) and 100 mg (0.22mmol), mmol) Reaction conditions: A mixture of the corresponding 4-chloropyridine derivative (8.12 mmol), 4-methoxyaniline of Cu(I)4-methoxyaniline supported on weakly acidic cation-exchanger resin was refluxed in100 isopropyl alcohol ofions Cu(I) ions on weakly acidic cation-exchanger resin was refluxed in(0.22 isopropyl alcohol 4-methoxyaniline (9.74 mmol), anhydrous potassium carbonate (3.45 g, 25 mmol) and 100 mg (0.22 mmol) 4-methoxyaniline (9.74 mmol), anhydrous potassium carbonate (3.45 g, 25 mmol) and 100 mg (0.22 mmol) of Cu(I) ions onconditions weakly acidic cation-exchanger resin was refluxed in isopropyl alcohol alcohol Cu(I) ions on weakly acidicatmosphere. cation-exchanger resin was refluxed in isopropyl (40anhydrous mL) of for 24supported h for in conditions of an open atmosphere. (40 mL) 24supported h in of an open (9.74 mmol), potassium carbonate (3.45 g, 25 mmol) and 100 mg (0.22 mmol) of Cu(I) ions supported of Cu(I) ions onconditions weakly acidic cation-exchanger resin was refluxed in isopropyl alcohol alcohol Cu(I) ions weakly acidicatmosphere. cation-exchanger resin was refluxed in isopropyl mL) of for 24supported h for in conditions of on an open atmosphere. (40 mL) 24supported h in of an open on weakly (40 acidic cation-exchanger resin was refluxed in isopropyl alcohol (40 mL) for 24 h in conditions of an (40 mL)(40 for 24 h for in conditions of an open atmosphere. mL) 24 h in conditions of an open atmosphere.

3. Materials and Methods 3. Materials and Methods open atmosphere.

3. Materials and Methods 3. Materials and Methods 3. Materials andreagents Methods Materials andpurchased Methods All3.reagents were from commercial suppliers (Sigma-Aldrich, Merck, Merck, Acros Organics, All were purchased from commercial suppliers (Sigma-Aldrich, Acros Organics, All reagents were purchased from commercial suppliers (Sigma-Aldrich, Merck, Acros Organics, All reagents were purchased from commercial suppliers (Sigma-Aldrich, Merck, Acros Organics, ® C104 ®Plus, Diegem, Belgium) and were used without further purification. Purolite macroporous Diegem, Belgium) andpurchased were used without further purification. Purolite C104 Plus, macroporous AllDiegem, reagents were purchased from commercial suppliers (Sigma-Aldrich, Merck, Acros Organics, All reagents were from commercial suppliers (Sigma-Aldrich, Merck, Acros Organics, ® ® 3. MaterialsDiegem, and Methods Belgium) and were used without further purification. Purolite C104 Plus, macroporous Belgium) and weredivinylbenzene used divinylbenzene withoutcrosslinked furthercrosslinked purification. Purolite C104 Plus,4.5 macroporous weakly acidic cation exchange resin, polyacrylic, total capacity (min.) eq/L weakly acidic cation exchange resin, polyacrylic, total capacity (min.) 4.5 eq/L ® C104 ®Plus, Diegem, Belgium) and were used without furthercrosslinked purification. Purolite macroporous Diegem, Belgium) and weredivinylbenzene used divinylbenzene without further purification. Purolite C104 Plus,4.5 macroporous weakly acidic cation exchange resin, polyacrylic, total capacity (min.) weakly acidic cation exchange resin, crosslinked polyacrylic, total capacity (min.) 4.5toeq/L +-form), +-form), (H shipping weight (approx.) 740–780 g/L [27]. All[27]. ofcrosslinked the solvents were purified according toeq/L the4.5 (H shipping weight (approx.) 740–780 g/L All of thepolyacrylic, solvents were purified according the weakly acidic cation exchange resin, divinylbenzene crosslinked polyacrylic, total capacity (min.) 4.5 eq/L weakly acidic cation exchange resin, divinylbenzene total capacity (min.) +-form), +-form), All reagents were purchased from commercial suppliers (Sigma-Aldrich, Merck, Acros Organics, (H shipping weight (approx.) 740–780 g/L [27]. All[27]. of the were TLC purified according to 60 the (H shipping weight (approx.) 740–780 g/L Allsolvents of(aluminum the plates solvents were purified according toeq/L the standard methods. The reactions were monitored byg/L TLC (aluminum Silica gel 60according F254 byF254 standard methods. The reactions were monitored by TLC plates TLC Silica gel by +-form), +-form), (H shipping weight (approx.) 740–780 g/L [27]. All of the solvents were purified according to the (H shipping weight (approx.) 740–780 [27]. All of the solvents were purified to the ®60 standard methods. The reactions were monitored byUV TLC (aluminum plates TLC Silica gel F254 byPlus, standard methods. The reactions were monitored by TLC (aluminum plates TLC Silica gel 60 F254 by macroporous Merck), spots were detected using ninhydrin and/or lamp CAMAG. Melting points were measured Merck), spots were detected using ninhydrin and/or UV lamp CAMAG. Melting points were measured Diegem, Belgium) and were used without further purification. Purolite C104 standard methods. The reactions were monitored byUV TLC (aluminum plates TLC Silica gel 60 F254 byF254 by standard methods. The reactions were monitored by TLC (aluminum plates TLC Silica gel 60 Merck), spots were detected using ninhydrin and/or lamp CAMAG. Melting points were measured Merck), spots were detected using ninhydrin and/or UV lamp CAMAG. Melting points were measured on Boetius apparatus PHMK 05 (VEB Nagema, Dresden, Germany). NMR spectra were on Boetius apparatus PHMK 05Kombinat (VEB Kombinat Nagema, Dresden, Germany). NMR spectra were Merck), spots were detected using ninhydrin and/or UV lamp CAMAG. Melting points were measured Merck), spots were detected using ninhydrin and/or UV lamp CAMAG. Melting points were measured weakly acidic cation exchange resin, divinylbenzene crosslinked polyacrylic, total capacity (min) on Boetius apparatus PHMK 05 (VEB Kombinat Nagema, Dresden, Germany). NMR spectra were on Boetius apparatus PHMK 05 (VEB Kombinat Nagema, Dresden, Germany). NMR spectra were TM 300 TM 300 obtained from a from Bruker Avance NMR III MHz and Bruker Avance III™Germany). 500 MHz (Leiderdorp, obtained aPHMK Bruker Avance NMR III MHz and Bruker Avance III™ 500spectra MHz spectra (Leiderdorp, on Boetius apparatus 05 (VEB Kombinat Nagema, Dresden, Germany). NMR were on Boetius apparatus PHMK 05 (VEB Kombinat Nagema, Dresden, NMR were TM TM + from a from Bruker Avance NMR III 300 and Bruker Avance III™ collected 500 MHz (Leiderdorp, obtained a Bruker Avance NMR IIIMHz 300740–780 MHz and spectra Bruker Avance III™ 500 MHz (Leiderdorp, 4.5 eq/L (Hobtained -form), shipping weight (approx.) g/L [27]. All of the solvents were purified The Netherland), using wideband probe BBFO. Infrared spectra were collected on Bruker Tensor 27 The Netherland), using wideband probe BBFO. Infrared were on Bruker Tensor 27 TM 300 TM 300 obtained from a from Bruker Avance NMR III and Bruker Avance III™ collected 500 MHz (Leiderdorp, obtained a Bruker Avance NMR IIIMHz MHz and spectra Bruker Avance III™ 500 MHz (Leiderdorp, The Netherland), using wideband probe BBFO. Infrared spectra were collected on Bruker Tensor 27 were The Netherland), using wideband probe BBFO. Infrared were on Bruker Tensor 27 spectrometer. Samples were measured in the form of KBr pellets. High resolution mass spectra were spectrometer. Samples were measured in the form of KBr pellets. High resolution mass spectra The Netherland), using wideband probe BBFO. Infrared spectra were collected onby Bruker Tensor 27 were The Netherland), using wideband probe BBFO. Infrared were collected on Bruker Tensor 27 according to the standard methods. The reactions were monitored TLC (aluminum plates TLC spectrometer. Samples were measured in TOF the form KBr pellets. High resolution mass spectra were spectrometer. Samples were measured in theofform of(Santa KBrspectra pellets. High resolution mass spectra obtained on Agilent 6224 Accurate-Mass spectrometer Clara, CA, USA). obtained on Agilent 6224 Accurate-Mass TOF spectrometer (Santa Clara, CA, USA). spectrometer. Samples were measured inTOF the form KBr of pellets. High resolution mass spectra were were Samples were measured in theofform KBr pellets. High resolution mass spectra on Agilent 6224 Accurate-Mass spectrometer (Santa Clara, CA, USA). obtained on Agilent 6224 Accurate-Mass TOF spectrometer (Santa Clara, CA, USA). Silica gel 60obtained F254spectrometer. by Merck), spots were detected using ninhydrin and/or UV lamp CAMAG. Melting obtained on Agilent 6224 Accurate-Mass TOF spectrometer (Santa Clara, USA). obtained on Agilent 6224 Accurate-Mass TOF spectrometer (Santa CA, Clara, CA, USA). 3.1. Preparation of Catalysts 3.1. Preparation of Catalysts points were3.1. measured on Boetius apparatus PHMK 05 (VEB Kombinat Nagema, Dresden, Germany). Preparation of Catalysts 3.1. Preparation of Catalysts ® C104 ® + form 3.1. Preparation of Catalysts 3.1. Preparation of Catalysts TMin Purolite Plus resin Na form amount of 75.0NMR g was water (200 mL). Cupric Purolite C104 Plusinresin in Nain in amount of 75.0 stirred gIII was stirred inMHz water (200 mL). Cupric Avance III™ NMR spectra were obtained from a++ Bruker Avance 300 and Bruker ® C104 ® + form Purolite Plus resin inresin Na form amount of in 75.0 gmL) was stirred in water (200 Cupric Purolite C104 Plus indissolved Nain inwater amount of 75.0 gmL) was stirred in water (200 mL). Cupric acetate monohydrate (49.9 g,Plus 250 mmol) inin (750 was mixed with aqueous ammonia acetate monohydrate (49.9 g, 250 mmol) dissolved water (750 was mixed withmL). aqueous ammonia ® C104 + in ®Plus + form Purolite resin in Na form in amount of 75.0 g was stirred in water (200 mL). Cupric Purolite C104 resin Na amount of 75.0 g was stirred in water (200 mL). Cupric acetate monohydrate (49.9 250 mmol) in water mL) was mixed aqueous ammonia acetate monohydrate (49.9 g,1255 250 dissolved mmol) dissolved in(750 water (750 mL) was mixed with aqueous ammonia 500 MHz (Leiderdorp, The Netherland), using wideband probe BBFO. Infrared spectra solution (28 w/w %, w/w 85 mL, 1255 mmol) under good stirring. Furthermore, the with dark blue solution was solution (28 %,g, 85 mL, mmol) under good stirring. Furthermore, the dark blue solution waswere collected acetate acetate monohydrate (49.9 g,85 250 mmol) in water mL) was mixed aqueous ammonia monohydrate (49.9 g,1255 250 dissolved mmol) dissolved in(750 water (750 mL) was mixed with aqueous ammonia solution (28 w/w %,suspension 85 mL, 1255 mmol) under good stirring. Furthermore, the with dark blue solution was solution (28 w/w %,suspension mL, mmol) under good stirring. Furthermore, the dark blue solution was added to the resin and stirred for 30 min. Then the aqueous phase was decanted and the added to the resin and stirred for 30 min. Then the aqueous phase was decanted and the on Bruker Tensor 27 spectrometer. Samples were measured in the form of KBr pellets. High resolution solution (28 w/w %,suspension 85 mL, 1255 mmol) under good Furthermore, the dark blue solution was solution w/w %,suspension 85 mL, 1255 mmol) under good stirring. Furthermore, the dark blue solution added to the resin and stirred forThe 30 min. Then the aqueous phase was decanted and thesolution added to(28 the resin and stirred forstirring. 30 min. Then the aqueous phase was decanted andwas the blue solid washed twice with water mL). resin was then stirred for 30 min in the water solution blue solid washed twice with(300 water (300 mL). The resin was then stirred for 30 min in the water added to the resin suspension and stirred for 30 min. Then the aqueous phase was decanted and the added to the resin suspension and stirred for 30 min. Then the aqueous phase was decanted and the mass spectrablue were obtained on Agilent 6224 Accurate-Mass TOF spectrometer (Santa Clara, CA, USA). solid washed twice with water mL). The resin was stirred min inuntil the solution blue solidcontaining washed twice with(300 water (300 mL). The resin was then stirred for 30 minwater in the water solution (250 mL) containing hydroxylammonium chloride (29.9 g, 430then mmol) at 50for °C30 the blue color of resinsolution (250 mL) hydroxylammonium chloride (29.9 g, 430 mmol) atuntil 50 °C the blue color of resin blue mL) solid washed twice with water mL). The resin was stirred 30 min inuntil the solution blue solidcontaining washed twice with(300 water (300 mL). The resin was then stirred for 30 minwater in the water (250 containing hydroxylammonium chloride (29.9 g, 430then mmol) at 50for °C until the blue color of resin (250 mL) hydroxylammonium chloride (29.9 g, 430 mmol) at 50 °C the blue color of resin changed to light gray. After that, the solution was decanted, the solid residue washed twice with changed to light gray. After that, the solution was decanted, the solid residue washed twice with (250 mL) containing hydroxylammonium chloride (29.9decanted, g,was 430 decanted, mmol) at 50the °C until the bluethe color ofcolor resin (250 mL) containing hydroxylammonium chloride (29.9 g, 430 mmol) at 50 °C until blue of resin changed tomL), light After that, the solution was the solid residue washed twice with changed togray. light gray. After that, the solution solid residue washed twice with water twice with methanol (150 mL) and dried indried vacuum. The copper content determined water (250 mL), twice with methanol (150 mL) and in vacuum. Theresidue copper content determined 3.1. Preparation of(250 Catalysts changed tomL), light After that, the solution was decanted, the solid washedcontent twice with changed togray. light gray. After that, the solution was decanted, theresidue solid washed twice with water (250 twice with methanol (150 mL) and dried in vacuum. The copper content determined water (250 mL), twice with methanol (150 mL) and dried in vacuum. The copper determined by flame atomic absorption spectrometry was approximately 2.2 mmol of Cu/1 g of dry catalyst. by flame atomic absorption spectrometry was approximately 2.2 mmol of Cu/1 g of dry catalyst. water (250 mL), twice methanol (150 was mL) and dried vacuum. Theof copper content determined water (250 mL),with twice with methanol (150 mL) andindried vacuum. Theofgcopper determined by absorption spectrometry approximately 2.2inmmol Cu/1 of drygcontent catalyst. byatomic flame atomic absorption spectrometry was approximately 2.2 mmol Cu/1 of dry catalyst. ®flame + form Purolite C104 Plus resin in Na in approximately amount of2.2 75.0 was stirred in water (200 mL). by flame absorption spectrometry was approximately 2.2 mmol of Cu/1g of dryg catalyst. byatomic flame atomic absorption spectrometry was mmol ofg Cu/1 of dry catalyst.

Cupric acetate monohydrate (49.9 g, 250 mmol) dissolved in water (750 mL) was mixed with aqueous ammonia solution (28 w/w %, 85 mL, 1255 mmol) under good stirring. Furthermore, the dark blue solution was added to the resin suspension and stirred for 30 min. Then the aqueous phase was decanted and the blue solid washed twice with water (300 mL). The resin was then stirred for 30 min in the water solution (250 mL) containing hydroxylammonium chloride (29.9 g, 430 mmol) at 50 ◦ C until the blue color of resin changed to light gray. After that, the solution was decanted, the solid residue

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washed twice with water (250 mL), twice with methanol (150 mL) and dried in vacuum. The copper content determined by flame atomic absorption spectrometry was approximately 2.2 mmol of Cu/1 g of dry catalyst. 3.2. General Synthetic Procedure for C-N Coupling of Aryl Amine with 4-Chloropyridin-1-ium Chloride A mixture of the corresponding aryl amine (9.74 mmol), 4-chloropyridin-1-ium chloride (1.21 g, 8.12 mmol), anhydrous potassium carbonate (3.45 g, 25 mmol) and supported Cu(I) catalyst (100 mg, 0.22 mmol of Cu, 2.7 mol % of Cu) was refluxed in isopropyl alcohol (40 mL) for 24 h under open atmosphere conditions. After 24 h, reaction mixture was filtered to remove potassium salts and catalyst. The solid was stirred in 50 mL of water until dissolution of potassium salts, catalyst was filtered off, washed twice with water (10 mL), methanol (10 mL), dried in vacuum and stored for further use. Diethyl ether (100 mL) was added to the product containing filtrate and the solution was then washed with 100 mL of water (three times). Organic phase was dried using anhydrous sodium sulfate and solvents were removed under reduced pressure. Product(s) was/were separated by flash chromatography on silica gel using methanol-dichloromethane (1:9) mixture as a mobile phase. Yields of products are listed in Table 2. 3.3. Synthesis of 4-Chloro-3,5-dimethylpyridin-1-ium Chloride The mixture of 3,5-lutidine (5.0 g, 46.7 mmol) and thionyl chloride (10 mL, 137 mmol) was refluxed for 24 h under argon atmosphere. After 24 h, the reaction mixture was cooled and 40 mL of toluene were added. Twenty-milliliter volumes of the mixture were distilled under vacuum. The brown precipitate was collected by filtration. The crude product was recrystallized from methanol [28]. Yield: 60%, m.p. 130 ◦ C. Melting point not reported in literature. 3.4. Synthesis of 4-Chloro-1-methylpyridin-1-ium Iodide 4-Chloropyridin-1-ium chloride (3 g, 19.99 mmol) was neutralized by 0.5 M KOH in ice cold water. Subsequently 4-chloropyridine was extracted into cold dichlomethane, which was later removed under reduced pressure at 0 ◦ C. Excess of methyl iodide was added into the resultant 4-chloropyridine and solution was stirred for 20 h at 0 ◦ C in order to get 98% yield of 4-chloro-1-methylpyridinium iodide, m.p. 161 ◦ C (dichloromethane), literature 156–159 ◦ C (diethyl ether: methanol) [29]. 3.5. General Synthetic Procedure for C-N Coupling of Selected 4-Chloropyridine Derivatives with 4-Methoxyaniline A mixture of the corresponding 4-chloropyridine derivative (8.12 mmol), 4-methoxyaniline (1.19 g, 9.74 mmol), anhydrous potassium carbonate (3.45 g, 25 mmol) and supported Cu(I) catalyst (100 mg, 0.22 mmol of Cu, 2.7 mol % of Cu) was refluxed in isopropyl alcohol (40 mL) for 24 h under open atmosphere conditions. After 24 h, reaction mixture was filtered to remove potassium salts and catalyst. The solid was stirred in 50 mL of water until dissolution of potassium salts, catalyst was filtered off, washed twice with water (10 mL), methanol (10 mL), dried in vacuum and stored for further use. Diethyl ether (100 mL) was added to the product containing filtrate and the solution was then washed with 100 mL of water (three times). Organic phase was dried using anhydrous sodium sulfate and solvents were removed under reduced pressure. Product(s) was/were separated by flash chromatography on silica gel using methanol-dichloromethane (1:9) mixture as a mobile phase. Yields of products see Table 3. 3.6. Synthesis of 1-(Pyrid-4-yl)piperazine 4-Chloropyridin-1-ium chloride (1.5 g, 10 mmol) was dissolved in 100 ml of isopropyl alcohol at 60 ◦ C. Piperazine (2.15 g, 25 mmol) and supported Cu(I) catalyst (100 mg, 0.22 mmol) was added into the resulted solution. The reaction mixture was refluxed for 13 h and monitored by TLC on silica gel plates, methanol was used as a mobile phase and spots were developed by ninhydrin.

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After the completion of a reaction, the reaction mixture was cooled to 5–10 ◦ C, the precipitated piperazine-1,4-diium dichloride was filtered off together with the catalyst, the filtrate was filtered with the addition of active carbon, and the solvent distilled off in vacuum to dryness. The residue of crude 1-(pyrid-4-yl)piperazine was recrystallized from n-heptane with the addition of silica gel. The yield of the reaction was 11.5 g (70%) of 1-(pyridin-4-yl)piperazine and the purity was determined by gas chromatography and achieved 99.1%. The insoluble residue during crystallization of the crude product was crystallized in boiling n-heptane. The filtrate was then concentrated to 1/3 of the original volume and allowed to crystallize at 5–10 ◦ C overnight. It gave an additional yield 2.5 g (15.3%) of 1-(pyrid-4-yl)piperazine and its purity of 97.8% was determined by gas chromatography as well. 4. Conclusions In conclusion, we found that recyclable copper(I) supported on weakly acidic polyacrylate resin catalyzes C-N cross coupling reaction in the absence of additional ligand. Described supported system catalyzes C-N cross coupling reactions of 4-chloropyridinium chloride with anilines containing electron donating (EDG) or electron withdrawing (EWG) groups, naphthalen-2-amine and piperazine, efficiently. C-N cross coupling gave two types of products, i.e., N-(pyridin-4-yl)benzene amines and/or N,N-bis(pyridine-4-yl)benzene amines depends on electronic effect on aniline and type of base used. A molar excess of piperazine as a base used in the case of coupling reaction realized between piperazine and 4-chloropyridinium chloride. Only formation of the 1-(pyridin-4-yl)piperazine in very good yield was observed as far as this reaction was realized in isopropyl alcohol. Synthesis in methanol or ethanol as solvents gave in addition to target 1-(pyridin-4-yl)piperazine product the corresponding 4-methoxy- or 4-ethoxypyridine. C-N cross coupling reactions of 4-methoxyaniline with 4-chloro-1-methylpyridinium iodide shows better activity than that with 4-chloropyridinium chloride. There was no C-N cross coupling reaction observed with 4-chloro-3,5-dimethylpyridine and 4-methoxyaniline. The applied novel supported catalytic Cu(I) system is very stable, insensitive to moisture and atmospheric oxygen. Hence, the described C-N coupling reactions can be carried out under open atmosphere and generally mild conditions. The applied Cu(I) catalyst is less toxic, economical, and easily preparable, separable, and recyclable (more than twenty times at full conversion of the starting 4-chloropyridinium chloride and the same reaction time). Therefore, the studied syntheses may be regarded as environmentally clean and green processes. Supplementary Materials: Supplementary materials can be accessed at: http://www.mdpi.com/1420-3049/22/ 1/2/s1. Acknowledgments: This work was supported by the Technological agency of the Czech Republic, grant number TA02010144. Author Contributions: Nitin Kore and Pavel Pazdera conceived and designed the experiments. Nitin Kore performed the experiment and analyzed the data. Nitin Kore and Pavel Pazdera wrote the paper. Conflicts of Interest: The authors declare no conflict of interest.

References 1. 2. 3.

Gujadhur, R.K.; Venkataraman, D.; Kintigh, J.T. Formation of arylnitrogen bonds using a soluble copper(I) catalyst. Tetrahedron Lett. 2001, 42, 4791–4793. [CrossRef] Gujadhur, R.K.; Bates, C.G.; Venkataraman, D. Formation of aryl−nitrogen, aryl−oxygen, and aryl−carbon bonds using well-defined copper(I)-based catalysts. Org. Lett. 2001, 3, 4315–4317. [CrossRef] [PubMed] Kiyomori, A.; Marcoux, J.F.; Buchwald, S.L. An efficient copper-catalyzed coupling of aryl halides with imidazoles. Tetrahedron Lett. 1999, 40, 2657–2660. [CrossRef]

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4.

5. 6. 7. 8. 9. 10.

11. 12.

13. 14.

15. 16.

17. 18. 19.

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Sample Availability: Samples of the all compounds are available from the authors. © 2016 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC-BY) license (http://creativecommons.org/licenses/by/4.0/).