NiCl2·6H2O as recyclable heterogeneous catalyst for N-arylation of amines and NH-heterocycles under microwave exposure

Article abstract of DOI:10.1016/j.tetlet.2012.02.081

NiCl₂·6H₂O has been proven to be an effective catalyst for the coupling of amines with aryl iodides without ligand under solvent-free conditions employing microwave irradiation. Reactions cleanly result in coupled products in a short reaction time. The catalyst, being heterogeneous, is recovered by filtration and is recyclable.

Full text of DOI:10.1016/j.tetlet.2012.02.081

Tetrahedron Letters 53 (2012) 2218–2221
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
NiCl2ꢀ6H2O as recyclable heterogeneous catalyst for N-arylation of amines
and NH-heterocycles under microwave exposure
⇑
Amit Kumar Gupta, G. Tirumaleswara Rao, Krishna Nand Singh
Department of Chemistry, Faculty of Science, Banaras Hindu University, Varanasi 221005, India
a r t i c l e i n f o
a b s t r a c t
Article history:
NiCl2ꢀ6H2O has been proven to be an effective catalyst for the coupling of amines with aryl iodides with-
out ligand under solvent-free conditions employing microwave irradiation. Reactions cleanly result in
coupled products in a short reaction time. The catalyst, being heterogeneous, is recovered by filtration
and is recyclable.
Received 4 January 2012
Revised 15 February 2012
Accepted 16 February 2012
Available online 24 February 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Microwave
N-arylation
Ni-catalysis
Solvent-free
The use of microwave energy to heat chemical reactions has be-
come an increasingly popular technique in the scientific commu-
nity which is evidenced by a large number of review articles and
books published on this subject.1,2 In many instances, controlled
microwave heating under sealed vessel conditions has been shown
to dramatically reduce reaction times, increase product yields, and
enhance product purities by reducing unwanted side reactions
compared to conventional synthetic methods. The advantages of
this technology have not only been exploited for organic synthesis
and in the context of medicinal chemistry/drug discovery,3 but
have also penetrated the fields such as polymer synthesis,4 mate-
rial science,5 nanotechnology,6 and biochemical processes.7
Transition metal-catalyzed cross-coupling reactions of aryl ha-
lides with various nucleophilic compounds are now among the
most prominent synthetic methods for the formation of carbon–
heteroatom bonds. Among these, the formation of C–N bond has
received much attention that finds wide applications in the synthe-
sis of many substances such as drugs, materials, natural products,
agrochemicals, and optical devices.8 Exclusively, these reactions
are performed under copper catalysis (Ullmann type reactions)9
or palladium catalysis (Buchwald–Hartwig reactions).10 Although
significant progress has been made with regard to these reactions,
there continues to be an increasing demand for low-cost and envi-
ronment-friendly catalysts which have attracted other transition
metals like iron and nickel in the field.
Ni(0) associated with 1,10-bis(diphenylphosphino)ferrocene or
1,10-phenanthroline for the synthesis of aryl amines.11 Till then a
number of articles regarding nickel-catalysis for C–N bond forma-
tion have been published.12 But nickel chemistry does not enjoy
the fame as of palladium and copper and thus demands more stud-
ies to be made in the field. In view of the above and as a part of our
ongoing research on the development of efficient protocols in or-
ganic synthesis,13 we report herein a ligand and solvent-free Ni(II)
catalyzed coupling of aryl halides with different aromatic, aliphatic
and heterocyclic amines under controlled microwave protocol
(Scheme 1).
As shown in Table 1, our experiments for the optimal conditions
began with the coupling of iodobenzene with aniline taking vari-
ous nickel salts as catalyst. The preliminary findings proved
NiCl2ꢀ6H2O to be the most effective for the reaction undertaken
(Table 1, entries 1–4). Then, we probed the solvent effect on the
reaction and to our delight we hit upon a solvent-free reaction
which is far superior to any of the solvents used in the reaction (Ta-
ble 1, entries 4–13). Some ligands were also incorporated in the
reaction but surprisingly none of them could match the yield under
R1
X
H
N
N
10 mol % NiCl2.6H2O
R2
Y
Y
The first report regarding nickel catalyzed C–N coupling was
produced by Buchwald in the form of cyclooctadiene complex of
R1
R2
1.4 eqvt Et3N, MW, 20 min
Z
Z
1
2
3
⇑
Corresponding author. Tel.: +91 542 6702485; fax: +91 542 2368127.
E-mail addresses: knsinghbhu@yahoo.co.in, knsingh@bhu.ac.in (K.N. Singh).
Scheme 1. Coupling of aryl halides with amines and NH-heterocycles.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2012.02.081

A. K. Gupta et al. / Tetrahedron Letters 53 (2012) 2218–2221
2219
Table 1
Optimization of reaction conditionsa
b
Entry
Catalyst (mol %)
Solvent
Ligand
Base
Temp (°C)
Time (min)
Yield (%)
1
2
3
4
5
6
7
8
Ni(OAc)2.4H2O (20)
NiSO4 (20)
Ni(NO3)2 (20)
DMSO
DMSO
DMSO
DMSO
Toluene
Acetonitrile
Ethanol
DMF
Water
Dioxane
Ethylene glycol
NMP
—
—
—
—
—
—
—
—
—
—
—
—
—
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
120
120
120
120
120
120
120
120
120
120
120
120
120
120
20
20
20
20
20
20
20
20
20
20
20
20
20
20
38
44
35
62
16
23
nr
Trace
nr
Trace
38
32
78
45
NiCl2ꢀ6H2O (20)
NiCl2ꢀ6H2O (20)
NiCl2ꢀ6H2O (20)
NiCl2ꢀ6H2O (20)
NiCl2ꢀ6H2O (20)
NiCl2ꢀ6H2O (20)
NiCl2ꢀ6H2O (20)
NiCl2ꢀ6H2O (20)
NiCl2ꢀ6H2O (20)
NiCl2ꢀ6H2O (20)
NiCl2ꢀ6H2O (20)
NiCl2ꢀ6H2O (20)
NiCl2ꢀ6H2O (20)
NiCl2ꢀ6H2O (20)
NiCl2ꢀ6H2O (20)
NiCl2ꢀ6H2O (20)
NiCl2ꢀ6H2O (20)
NiCl2ꢀ6H2O (20)
NiCl2ꢀ6H2O (20)
NiCl2ꢀ6H2O (20)
NiCl2ꢀ6H2O (20)
NiCl2ꢀ6H2O (20)
NiCl2ꢀ6H2O (20)
NiCl2ꢀ6H2O (20)
NiCl2ꢀ6H2O (20)
NiCl2ꢀ6H2O (20)
NiCl2ꢀ6H2O (20)
NiCl2ꢀ6H2O (20)
NiCl2ꢀ6H2O (30)
NiCl2ꢀ6H2O (10)
NiCl2ꢀ6H2O (5)
—
9
10
11
12
13
14
—
—
L-Proline
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
Ethylenediamine
1,10-Phenenthroline
Ethylacetoacetate
Et3N
Et3N
Et3N
Na2CO3
KOH
NaOH
Pyridine
—
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
120
120
120
120
120
120
120
120
120
120
120
110
130
140
130
130
130
130
130
130
130
130
20
20
20
20
20
20
20
20
20
20
20
20
20
20
10
30
40
20
20
20
20
60
54
32
43
nr
nr
nr
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
24
nr
77c
68d
78e
57
85
83
52
82
76
85
85
81
nr
NiCl2ꢀ6H2O (10)
17f
The bold values in Table 1 signify the optimized reaction conditions.
a
Reaction using 1 mmol iodobenzene, 1.5 mmol aniline and 1.4 equiv base.
Isolated yield.
Reaction performed with 2 equiv of Et3N.
Reaction using 1.2 mmol aniline.
Reaction using 2 mmol aniline.
Reaction by conventional heating.
b
c
d
e
f
Table 2
Coupling of aryl halides with various amines and NH-heterocycles14
a
Entry
1
Aryl halide
Amine
Product
Temp (°C)
Yield (%)
X
NH2
NH
NH
120
140
140
160
85 (X = I)
62 (X = Br)
Trace (X = Cl)
34 (X = Cl)
3a
3b
X= I, Br, Cl
I
92b
89c
88d
86e
NH2
2
125
I
I
I
I
NH2
NH
NH
NH
NH
3
4
5
6
3c
3d
3e
3f
125
110
120
150
88
72
70
MeO
Cl
OMe
Cl
NH2
NH2
Br
Br
NH2
75
NO2
O2N
(continued on next page)

2220
A. K. Gupta et al. / Tetrahedron Letters 53 (2012) 2218–2221
Table 2 (continued)
a
Entry
Aryl halide
Amine
Product
Temp (°C)
Yield (%)
I
NH
NH
NO2
7
8
3g
3h
150
78
56
O2N
Cl
NH2
NH2
I
I
Cl
Cl
150
150
140
Cl
Cl
Cl
NH
NH2
NH2
9
3i
3j
47
52
H2N
NH
I
N
10
N
NH2
X
140
140
140
160
72 (X = I)
57 (X = Br)
nr (X = Cl)
Trace (X = Cl)
N
N
11
12
3k
3l
N
H
X= I, Br, Cl
I
O
O
140
57
N
H
I
NH2
H
N
13
14
15
3m
3n
3o
150
160
140
62
I
I
NH2
NH
36
HN
N
N
N
Trace
I
N
16
17
18
3p
3b
3i
140
130
160
54
72
28
N
H
I
NH2
NH2
NH
NH
NH2
I
H2N
NH
I
NH2
NH2
19
20
21
3d
3q
3r
110
140
150
76
87
74
Cl
Cl
Cl
NH
O2N
NO2
Cl
O2N
NH
NO2
CF3
NH2
F3C
a
Isolated yield.
Fresh catalyst.
First cycle.
Second cycle.
b
c
d
e
Third cycle.
ligand-free conditions (Table 1, entries 14–17). Next, the role of the
base was examined and out of all the bases tried, triethylamine
was found to be the best (Table 1, entries 13, 18–21). A series of
experiments were performed at different temperatures and
130 °C was found to be optimum for the reaction. Finally the effect
of catalyst loading was examined and 10 mol % of the catalyst was
concluded to be the optimum to promote the reaction (Table 1, en-
tries 32–34). The model reaction was also carried out by conven-
tional heating which is not at all comparable to the microwave
conditions (Table 1, entry 36).
With the optimum reaction conditions (Table 1, entry 33) in
hand, the versatility of the reaction was extended to a number of
aryl halides with various arylamines, alkylamines and NH-hetero-
cycles. The outcome of the experiments is shown in Table 2.
A perusal of Table 2 reveals that almost all kinds of amines and
NH-heterocycles couple with iodobenzene in good to excellent
conversion (Table 2, entries 1–16). The aromatic amines with elec-
tron donating groups react more efficiently in comparison to those
bearing electron withdrawing groups (Table 2, entries 2–7). Ali-
phatic amines and NH-heterocycles also exhibit good conversion

A. K. Gupta et al. / Tetrahedron Letters 53 (2012) 2218–2221
2221
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in the reaction (Table 2, entries 11–16). The role of various aryl ha-
lides was also examined in the reaction using aniline as counter-
substrate and it was found that iodobenzene is more reactive than
bromobenzene. Chlorobenzene being reluctant, showed some
reactivity under harsh reaction conditions (Table 2, entry 1–11);
albeit, chloroderivatives with electron withdrawing groups readily
couple in the reaction (Table 2, entries 20 and 21).
It is worthwhile to note that the catalyst NiCl2ꢀ6H2O being
insoluble in the reaction mixture is easily recovered by simple fil-
tration and is reused three times without any significant diminu-
tion in its amount and activity (Table 2, entry 2).
In summary, we have developed a convenient, rapid, economi-
cal and environmentally friendly Ni(II) catalyzed protocol for the
N-arylation of amines with aryl halides under microwave irradia-
tion. The key features of the reaction are (1) solvent-free conditions
(2) no ligand needed (3) recoverable and recyclable catalyst (4) no
need of inert atmosphere and (5) very short reaction time and
operational simplicity.
Acknowledgment
We are thankful to the Department of Biotechnology, New Delhi
for financial assistance.
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2419–2422; (d) Raghuvanshi, D. S.; Singh, K. N. Synlett 2011, 373–377; (e)
Allam, B. K.; Singh, K. N. Synthesis 2011, 1125–1131.
References and notes
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14. General procedure for preparation of N-arylated amines 3: Aryl halide (1 mmol),
amine (1.5 mmol), NiCl2ꢀ6H2O (10 mol % relative to aryl halide) and
triethylamine (1.4 equiv) were taken in a 10 mL pressurized microwave vial
with snap on cap. The reaction mixture was subjected to microwave exposure
for 20 min at 300 W at appropriate temperature as indicated above. The
progress of the reaction was monitored by TLC (Thin Layer Chromatography).
After the reaction was completed, the reaction mixture was diluted with DCM
and the insoluble catalyst was recovered and recycled without loss of activity.
The filtrate was concentrated and subjected to column chromatography with
n-hexane and ethyl acetate (2–10% depending upon the product) as eluent to
afford the pure product.
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N-(p-Tolyl) phenyl amine (3b): colorless solid; mp 88 °C; IR (KBr):
m ;
3344 cmꢁ1
1H NMR (300 MHz, CDCl3): d 2.30 (s, 3H), 5.59 (s, 1H), 6.85 (t, J = 7.2 Hz, 1H),
6.99 (m, 4H), 7.07 (m, 2H), 7.20 (m, 2H); 13C NMR (75 MHz, CDCl3): d 20.7,
116.8, 118.9, 120.3, 129.3, 129.8, 130.9, 140.3, 143.9.
N-(4-Methoxyphenyl) aniline (3c): Colorless solid; mp 105 °C; IR (KBr):
m
3402 cmꢁ1 1H NMR (300 MHz, CDCl3): d 3.79 (s, 3H), 5.48 (s, 1H) 6.80–6.91 (m,
;
5H), 7.05–7.08 (m, 2H) 7.18–7.25 (m, 2H). 13C NMR (75 MHz, CDCl3): d 55.5,
114.6, 115.6, 119.5, 122.2, 129.3, 135.7, 145.1, 155.2.