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

Article abstract of DOI:10.3390/molecules22010002

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.

Full text of DOI:10.3390/molecules22010002

molecules
Article
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; kore_ns@yahoo.co.in
* Correspondence: pazdera@chemi.muni.cz; 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 [ ] and hydrazides [ ] as well. However, all above reported C-N coupling
5
6
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
www.mdpi.com/journal/molecules

Molecules 2017, 22, 2
2 of 11
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
64
8
0
23.6
2.9
0
Copper(I) iodide
No catalyst
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.

Molecules 2017, 22, 2
3 of 11
Scheme 1. C-N coupling reaction with 4-chloropyridin-1-ium chloride with substituted aniline.
R1–H/EDG/EWG; R2–H/Pyridine.
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-,
or 4-methoxyanilinem afforded products with the only one amino group hydrogen atom replaced in
64%–80% yield (Table 2, entries 1–2, 4–5).
Table 2. Comparison of pure product yields for different aromatic amines in C-N coupling reaction
with 4-chloropyridin-1-ium chloride in the presence of potassium carbonate as a base.
Entry
Amine
Product
Yield (%)
TON
1
80
29.5
2
3
78
22
28.7
8.1
4
5
68
64
25
23.6
6
7
12
40
4.4
14.7
8
9
46
47
45
16.9
17.3
16.6
10

Molecules 2017, 22, 2
4 of 11
Table 2. Cont.
Product
Entry
Amine
Yield (%)
TON
11
49
18
12
13
26
24
9.5
30.9
30
10
32
14
27.3
15
16
42
31
9
39
6
32.10
17
20
24

Molecules 2017, 22, 2
5 of 11
Table 2. Cont.
Product
Entry
Amine
Yield (%)
TON
6
18
31
39
42
19
20
32.4
4
65
24
Reaction conditions: A mixture of 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) was
refluxed in isopropyl alcohol (40 mL) for 24 h in open atmosphere conditions.
The synthetic process with sterically hindered o-substituted aniline, e.g., 2,5-dimethoxy- and
2,4-dimethylaniline, underwent replacement of one amine hydrogen atom in 22% and 12% yield,
respectively. Low yields of the reactions may be inflicted by steric hindrance of o-substitutes in the
molecule (Table 2, entries 3, 6).
The reaction with slightly deactivated substituted aniline, 4-chloro-, 4-bromo-, 4-iodo-,
4-fluoroaniline, and ethyl 4-aminobenzoate, underwent reaction with replacement of one amine
hydrogen in 26%–49% yield (Table 2, entries 8–12).
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
formation of C-N coupling product with replacement of the only hydrogen of aniline in comparatively
low yield concerning aniline consisting slightly deactivating group is similar to all previously reported
articles [6,10,15].
The reaction with aniline substituted by a strong electron withdrawing group, 2,4-dichloro,
4-trifluoromethyl, 4-cyano, 2-cyano, 3-nitro- and 4-nitroaniline, ended up in formation of novel
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).

Molecules 2017, 22, 2
6 of 11
Figure 1. Comparison of yields for different aromatic amines in C-N coupling reaction with
4-chloropyridine in the presence of K2CO3 as a base.
In the case of coupling reaction between piperazine and 4-chloropyridinium chloride, a molar
excess of piperazine as a base and isopropyl alcohol as a solvent were used. Only formation of the
1-(pyridin-4-yl)piperazine in very good yield was observed. If the reaction was carried out under
reflux in methanol or in ethanol, 4-methoxy- or 4-ethoxypyridine was formed due to competing
reaction in yield 22% and 18%, respectively. When using isopropyl alcohol, the above-mentioned
competitive C-O coupling reaction did not proceed at all apparently because of the presence of the
bulky isopropyl group and the low acidity of hydroxyl group. On the other hand, the application of
potassium hydroxide, carbonate or hydrogen carbonate as a base as well as temperature of boiling
solvent evoked decomposition of 4-chloropyridine in the course of synthesis.
To understand the chemistry of the coupling process, we decided to accomplish the
same reaction using KHCO3 as a weaker base than potassium carbonate. In the presence of
KHCO3 as a base, 4-(trifluoromethyl)aniline as well as 2-aminobenzonitrile yielded selectively
corresponding N-(pyridin-4-yl)benzene amines as the only product, while, in the cases of 2-nitroaniline,
2,4-dichloroaniline, 4-aminobenzonitrile, and 4-nitroaniline, formation of N-(pyridin-4-yl)benzene
amines as a major product together with N,N-bis(pyridin-4-yl)benzeneamines as a secondary product
was observed (Figure 2).
Figure 2. Comparison of yields for different aromatic amines in C-N coupling reaction with
4-chloropyridine in the presence of KHCO3 as a base.

Molecules 2017, 22, 2
7 of 11
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-chloro-
3,5-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).
4-Chloro-1-methylpyridinium iodide underwent reaction with 4-methoxyaniline under replacement of
one hydrogen atom 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 better activity than 4-chloropyridine.
Table 3. Comparison of yields for selected 4-chloropyridine derivatives in C-N coupling reaction
with 4-methoxyaniline.
Entry
4-Chloropyridine Derivative
Product
Yield (mol %)
TON
1
64
23.6
2
3
0
0
80
29.5
Reaction conditions: A mixture of the corresponding 4-chloropyridine derivative (8.12 mmol), 4-methoxyaniline
(9.74 mmol), anhydrous potassium carbonate (3.45 g, 25 mmol) and 100 mg (0.22 mmol) of Cu(I) ions supported
on weakly acidic cation-exchanger resin was refluxed in isopropyl alcohol (40 mL) for 24 h in conditions of an
open atmosphere.
3. Materials and Methods
All reagents were purchased from commercial suppliers (Sigma-Aldrich, Merck, Acros Organics,
Diegem, Belgium) and were used without further purification. Purolite® C104 Plus, macroporous
weakly acidic cation exchange resin, divinylbenzene crosslinked polyacrylic, total capacity (min)
4.5 eq/L (H+-form), shipping weight (approx.) 740–780 g/L [27]. All of the solvents were purified
according to the standard methods. The reactions were monitored by TLC (aluminum plates TLC
Silica gel 60 F254 by Merck), spots were detected using ninhydrin and/or UV lamp CAMAG. Melting
points were measured on Boetius apparatus PHMK 05 (VEB Kombinat Nagema, Dresden, Germany).
NMR spectra were obtained from a Bruker Avance NMR IIITM 300 MHz and Bruker Avance III
™
500 MHz (Leiderdorp, The Netherland), using wideband probe BBFO. Infrared spectra were collected
on Bruker Tensor 27 spectrometer. Samples were measured in the form of KBr pellets. High resolution
mass spectra were obtained on Agilent 6224 Accurate-Mass TOF spectrometer (Santa Clara, CA, USA).
3.1. Preparation of Catalysts
Purolite® C104 Plus resin in Na+ form in amount of 75.0 g was stirred in water (200 mL).
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

Molecules 2017, 22, 2
8 of 11
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.

Molecules 2017, 22, 2
9 of 11
◦
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]

Molecules 2017, 22, 2
10 of 11
4.
Klapars, A.; Antilla, J.C.; Huang, X.; Buchwald, S.L. A general and efficient copper catalyst for the amidation
of aryl halides and the N-arylation of nitrogen heterocycles. J. Am. Chem. Soc. 2001, 123, 7727–7729.
[CrossRef] [PubMed]
5.
6.
7.
8.
9.
Antilla, J.C.; Klapars, A.; Buchwald, S.L. The Copper-Catalyzed N-Arylation of Indoles. J. Am. Chem. Soc.
2002, 124, 11684–11688. [CrossRef] [PubMed]
Wolter, M.; Klapars, A.; Buchwald, S.L. Synthesis of N-aryl hydrazides by copper-catalyzed coupling of
hydrazides with aryl iodides. Org. Lett. 2001, 3, 3803–3805. [CrossRef] [PubMed]
Xu, H.; Wolf, C. Efficient copper-catalyzed coupling of aryl chlorides, bromides and iodides with aqueous
ammonia. Chem. Commun. 2009, 21, 3035–3037. [CrossRef] [PubMed]
Correa, A.; Bolm, C. Ligand-free copper-catalyzed N-arylation of nitrogen nucleophiles. Adv. Synth. Catal.
2007, 349, 2673–2676. [CrossRef]
Sperotto, E.; de Vries, J.G.; van Klink, G.P.M.; van Koten, G. Ligand-free copper(I) catalyzed N- and
O-arylation of aryl halides. Tetrahedron Lett. 2007, 48, 7366–7370. [CrossRef]
10. Jammi, S.; Sakthivel, S.; Rout, L.; Mukherjee, T.; Mandal, S.; Mitra, R.; Saha, P.; Punniyamurthy, T. CuO
nanoparticles catalyzed C-N, C-O, and C-S cross-coupling reactions: Scope and mechanism. J. Org. Chem.
2009, 74, 1971–1976. [CrossRef] [PubMed]
11. Rout, L.; Jammi, S.; Punniyamurthy, T. Novel CuO nanoparticle catalyzed C-N cross coupling of amines
with iodobenzene. Org. Lett. 2007, 9, 3397–3399. [CrossRef] [PubMed]
12. Likhar, P.R.; Roy, S.; Roy, M.; Kantam, M.L.; de, R.L. Silica immobilized copper complexes: Efficient and
reusable catalysts for N-arylation of N(H)-heterocycles and benzyl amines with aryl halides and arylboronic
acids. J. Mol. Catal. A Chem. 2007, 271, 57–62. [CrossRef]
13. Lechat, P.; Tesleff, S.; Bownan, W.C. Aminopyridines and Similarly Acting Drugs; Pergamon Press: Oxford,
UK, 1982.
14. Burgeson, J.R.; Moore, A.L.; Boutilier, J.K.; Cerruti, N.R.; Gharaibeh, D.N.; Lovejoy, C.E.; Amberg, S.M.;
Hruby, D.E.; Tyavanagimatt, S.R.; Allen, R.D.; et al. SAR analysis of a series of acylthiourea derivatives
possessing broad-spectrum antiviral activity. Bioorg. Med. Chem. Lett. 2012, 22, 4263–4272. [CrossRef]
[PubMed]
15. Schulte, J.P.; Tweedie, S.R. Palladium-catalyzed couplings of heteroaryl amines with aryl halides using
sodium phenolate as the stoichiometric base. Synlett 2007, 15, 2331–2336. [CrossRef]
16. Keddie, D.J.; Guerrero-Sanchez, C.; Moad, G.; Mulder, R.J.; Rizzardo, E.; Thang, S.H. Chain transfer kinetics
of acid/base switchable N-aryl-N-pyridyl dithiocarbamate RAFT agents in methyl acrylate, N-vinylcarbazole
and vinyl acetate polymerization. Macromolecules 2012, 45, 4205–4215. [CrossRef]
17. Barbaro, P.; Liguori, F. Ion exchange resins: Catalyst recovery and recycle. Chem. Rev. 2009, 109, 515–529.
[CrossRef] [PubMed]
18. Keiji, O.; Mutsumi, S. Method for Producing Hydroxylamine Compound Using Platinum Catalyst Fixed on
Ion-Exchange Resin. U.S. 020060106254 Al, 18 May 2006.
19. Herrmann, W.A.; Kratzer, R.M.; Bliimel, J.; Friedrich, H.B.; Fischer, R.W.; Apperley, D.C.; Mink, J.; Berkesi, O.
Polymer supported catalyst for the effective autoxidation of cumene to cumene hydroperoxide. J. Mol. Catal.
A Chem. 1997, 120, 109–116.
20. Yu, L.; Chen, D.; Li, J.; Wang, P.G. Preparation, characterization, and synthetic uses of Lanthanide(III)
catalysts supported on ion exchange resins. J. Org. Chem. 1997, 62, 3575–3581. [CrossRef]
21. Parkash, R.; Zpka, J. The reaction between copper(II) and cyanide ions. Microchem. J. 1972, 17, 309–317.
[CrossRef]
22. Zimmerman, L. Toxicity of copper and ascorbic acid to Serratia marcescens. J. Bacteriol. 1966, 91, 1537–1542.
[PubMed]
23. Labuda, J.; Korgova, E. Reaction of macrocyclic complex Cu(TAAB)2+ with hydroxylamine. Chem. Papers
1986, 40, 301–307.
24. Nguyen, L.M.; Dellinger, M.E.; Lee, J.T.; Quinlan, R.A.; Rheingold, A.L.; Pike, R.D. Convenient synthesis of
copper(I) thiolates and related compounds. Inorg. Chim. Acta. 2005, 358, 1331–1336. [CrossRef]
25. Dams, M.; Vsarman, E. The reduction of copper sulphate with hydroxyl amine. J. Am. Chem. Soc. 1909, 31,
637–640.

Molecules 2017, 22, 2
11 of 11
26. Shigetomi, Y.; Arimoto, R.; Nagahota, T. Reducing elution method for copper(II) in cation-exchange
chromatography by hydroxylamine hydrochloride solution. Talanta 1972, 19, 1210–1213. [CrossRef]
27. Purolite®. Available online: http://www.purolite.com/product/c104plus (accessed on 20 November 2016).
28. Zoghbi, M.; Chen, L. Synthesis of Pharmaceutically Useful Pyridine Derivatives. U.S. Patent 6437139,
20 August 2002.
29. Brenelli, E.C.S.; Moran, P.J.S. The reactivity of some primary amines in SN2Ar reactions with 2- and
4-chloro-1-methylpyridinium ions. J. Chem. Soc. Perkin Trans. 2 1989, 1219–1222. [CrossRef]
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/).