N-(Pyridin-2-yl)benzamide: Efficient ligand for the nickel catalyzed Chan-Lam cross-coupling reaction

Article abstract of DOI:10.1016/j.tetlet.2015.10.047

An efficient protocol for the Chan-Lam cross-coupling reactions of arylboronic acids with aryl or alkyl amines has been developed by employing simple N-(pyridin-2-yl)benzamide ligand with Ni(OAc)₂·4H₂O in the presence of TMG base. The reaction proceeded well with high yields by employing various N-nucleophiles at low catalytic loadings.

Full text of DOI:10.1016/j.tetlet.2015.10.047

Tetrahedron Letters xxx (2015) xxx–xxx
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N-(Pyridin-2-yl)benzamide: efficient ligand for the nickel catalyzed
Chan–Lam cross-coupling reaction
Srinivas Keesara
School of Chemistry, University of Hyderabad, Hyderabad 500046, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient protocol for the Chan–Lam cross-coupling reactions of arylboronic acids with aryl or alkyl
amines has been developed by employing simple N-(pyridin-2-yl)benzamide ligand with Ni
(OAc)2Á4H2O in the presence of TMG base. The reaction proceeded well with high yields by employing
various N-nucleophiles at low catalytic loadings.
Received 18 August 2015
Revised 13 October 2015
Accepted 14 October 2015
Available online xxxx
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
Chan–Lam
C–N coupling
Ni catalyst
TMG
Benzamide
Introduction
copper catalysts for Chan–Lam coupling reactions. We found some
reports with mixed transition metal catalysts. Sawant and co-
The discovery of the transition-metal-catalyzed Chan–Lam
cross-coupling reaction has taken innovative progress in synthetic
organic chemistry by providing highly applicable C–N bond
formations via the coupling of arylboronic acids with N-nucle-
ophiles.1 N-Aryl scaffold involving C–N bond forming reactions
are of high synthetic significance for various natural products,
agrochemicals, and pharmaceutical materials.2 Ullmann coupling
was the traditional method for the C–N bond forming reactions
between N-nucleophiles and aryl halides using stoichiometric
amounts of Cu salts at higher temperatures.3 Stille, Hartwig, and
Buchwald reported the C–N coupling of aryl halides and
nucleophilic primary/secondary amines by using Pd catalysts.4
Significant progress has been achieved in the past decade in the
copper and palladium catalyzed C–N bond forming reactions. The
high cost of palladium catalysts restricts their usage in industrial
applications. Some of the reported methods employed stoichio-
metric amounts of Cu for different active aryl donor reagents like
aryl silanes,5 aryl stannanes,6 aryl bismuth,7 and aryl lead
triacetates.8
workers described Cu–Mn bimetallic catalyst for N-arylated amine
synthesis from arylboronic acids and amines.11 Nasrollahzadeh
and co-workers reported copper and ligand free catalyst Fe@Pd
nanowires for the Chan–Lam coupling reaction.12 They used
3.0 mol % of the expensive Pd catalyst for efficient coupling of aryl
boronic acids with aryl amine. Until recently, nickel-based cata-
lysts were successfully applied to the above coupling reactions,
which are equal to copper catalysts in their catalytic activity. Singh
and co-workers developed the first Ni catalyst for the Chan–Lam
coupling reaction of arylboronic acids with N-nucleophiles using
bipyridyl ligand and DBU base.13 Singh and co-workers reported
the C–N coupling reaction with Ni(II) complexes of bis-(2-acetylth-
iophene)oxaloyldihydrazone.14 Shi and co-workers reported the
arylation of amines by Ni(II)-thiolate complexes.15 All the reported
methods used 15–20 mol % of Ni catalyst for biarylamine synthesis.
Few reports on the above named reaction offer a wide scope for
researchers to improve the efficiency of the Ni catalyst. Therefore,
it is essential to develop more simple and efficient Ni catalytic
systems for Chan–Lam cross coupling reaction. Herein, we report
N-(pyridin-2-yl)benzamide as efficient ligand for the Ni-catalyzed
Chan–Lam cross-coupling reaction of amines with arylboronic
acids.
In 1998, Chan and Lam reported the preparation of N-arylimines
from arylboronic acids using Cu catalysts under mild reaction con-
ditions providing
a valuable alternative to traditional cross-
couplings in the construction of C–N bonds.9 The use of low toxic
arylboronic acids has found wide applications in modern organic
synthesis.10 No other transition metal catalysts are as popular as
To develop an efficient Ni catalytic system for Chan–Lam cou-
pling reaction, initially we studied the different Ni(II)-salts with
N-(pyridin-2-yl)benzamide ligand (1a) using TMG (1,1,3,3-tetram-
ethylguanidine) as base in toluene at 60 °C. For this purpose, we
http://dx.doi.org/10.1016/j.tetlet.2015.10.047
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Please cite this article in press as: Keesara, S. Tetrahedron Lett. (2015), http://dx.doi.org/10.1016/j.tetlet.2015.10.047

2
S. Keesara / Tetrahedron Letters xxx (2015) xxx–xxx
Table 1
Table 3
Optimization of the N-arylation reaction of phenylboronic acid with anilinea
Coupling reactions of arylboronic acids with a variety of N-nucleophilesa
H
Ni(OAc)2 .4H2O/1a
R
R
NH2
B(OH)2 Ni(OAc)2 .4H2O/1a
N
Ar
NH Ar
NH2
+
B(OH)2
+
TMG, toluene
base, solvent
4aa-ao
2
3
2a
4aa
Yieldb (%)
3a
Entry
1
R
Ar
Product
Yieldb (%)
Entry
Ni(II) salt/1a
Base
Solvent
B(OH)2
B(OH)2
1
2
3
4
5
6
7
8
NiCl2Á6H2O/1a
TMG
TMG
TMG
TMG
K3PO4
K2CO3
LiOHÁH2O
Dabco
Et3N
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
CH3CN
Dioxane
Methanol
Water
5
H
H
H
4aa
84
80
Ni(NO3)2Á6H2O/1a
NiSO4Á7H2O/1a
40
10
84
Nr
Nr
Nr
Nr
Nr
Nr
73
31
Nr
Nr
Nr
22
Ni(OAc)2Á4H2O/1a
Ni(OAc)2Á4H2O/1a
Ni(OAc)2Á4H2O/1a
Ni(OAc)2Á4H2O/1a
Ni(OAc)2Á4H2O/1a
Ni(OAc)2Á4H2O/1a
Ni(OAc)2Á4H2O/1a
Ni(OAc)2Á4H2O/1a
Ni(OAc)2Á4H2O/1a
Ni(OAc)2Á4H2O/1a
Ni(OAc)2Á4H2O/1a
Ni(OAc)2Á4H2O/1a
Ni(OAc)2Á4H2O/1a
2
4ab
F
Cl
B(OH)2
B(OH)2
3
4
5
4ac
4ad
4ae
74
72
78
9
10
11
12
13
14
15
16
—
4-OMe
3-Me
TMG
TMG
TMG
TMG
TMG
TMG
B(OH)2
B(OH)2
DMSO
—
6
3-Me
4af
75
F
a
Reaction conditions: Phenylboronic acid (1 mmol), aniline (2 mmol), nickel(II)
salt (10 mol %), ligand 1a (20 mol %), base (2 mmol), solvent (1 mL) at 60 °C for 24 h.
Cl
B(OH)2
B(OH)2
7
8
3-Me
2-Me
4ag
4ah
70
76
b
Isolated yield based on arylboronic acid. Nr = no reaction.
B(OH)2
9
2-Me
2-Ac
2-Ac
4ai
4aj
4ak
72
71
72
O
S
F
N
N
H
N
N
H
N
H
HN N
O
N OH
B(OH)2
B(OH)2
MeO
10
11
1c
1a
1b
Figure 1. Structures of the designed amine ligands.
F
Cl
B(OH)2
B(OH)2
12
13
2-Ac
2-Br
4al
68
Table 2
Ni(OAc)2Á4H2O /ligand catalyzed N-arylation reaction of phenylboronic acid with
4am
74c
anilinea
B(OH)2
Entry Ni(II) salt (mol
%)
Ligand (mol
%)
Time
(h)
Temp
(°C)
Yieldb
(%)
14
15
2-Br
H
4an
4ao
70c
80
F
1
2
3
4
5
6
7
8
10
10
10
5
10
10
10
10
1a (20)
1b (20)
1c (20)
1a (10)
1a (20)
1a (20)
1a (20)
1a (20)
24
24
48
24
15
24
24
24
60
60
60
60
80
28
60
60
84
40
25
52
86
Nr
B(OH)2
a
Reaction conditions: arylboronic acid (1 mmol), N-nucleophile (2 mmol), cata-
lyst 10 mol % (Ni(OAc)2Á4H2O/1a 1:2), TMG (2 mmol), toluene (1 mL) at 60 °C for
44c
80d
24 h.
b
Isolated yield based on arylboronic acid.
c
Reaction time 30 h.
a
Reaction conditions: Phenylboronic acid (1 mmol), aniline (2 mmol), catalyst
(Ni(OAc)2. 4H2O/L 1:2), TMG (2 mmol), toluene (1 mL).
b
Isolated yield based on arylboronic acid.
Reaction with 1 equiv of aniline.
Reaction under nitrogen atmosphere.
c
TMG was found to be the best for our reaction conditions. We
observed from the above results that the TMG base has much affect
on the coupling. In contrast to other bases, the high pKa value and
strong basic nature of TMG might be the responsible factor for effi-
cient coupling.16 However, no reaction occurred in the absence of
base (entry 10). This clearly shows that the base plays a major role
in the coupling reaction. Next, we focused on the role of solvent for
this coupling reaction. It was observed that, among the various sol-
vents screened, only toluene, acetonitrile, and dioxane promoted
the coupling reaction (entries 4, 11, and 12). Poor or no coupling
product formation was observed in the presence of polar protic sol-
vents (like methanol, water) and DMSO (entries 13–15). Low yields
were observed, in the absence of solvent (entry 16). Thus toluene
found to be the best solvent to promote the coupling reaction.
d
chose phenylboronic acid and aniline as model substrates for the
above coupling reaction and the results are summarized in Table 1.
All the reactions were conducted with 10 mol % of Ni(II) salts and
20 mol % of ligand 1a. To find out a best combination, we have
screened various Ni(II) salts (NiCl2Á6H2O, Ni(NO3)2Á6H2O, NiSO4-
Á7H2O and Ni(OAc)2Á4H2O) with ligand 1a. Among these Ni(II) salts,
Ni(OAc)2Á4H2O was found to be most suitable for the combination
of ligand 1a with desired product yield of 84% (entry 4). We also
screened the coupling reaction with a variety of inorganic and
organic bases (entries 5–9). The organic non nucleophilic base
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S. Keesara / Tetrahedron Letters xxx (2015) xxx–xxx
3
Further, we studied the catalytic activity of Ni(OAc)2Á4H2O with
different types of ligands (1a–1c)17–19 (Fig. 1) for the Chan–Lam
coupling reaction between phenylboronic acid and aniline using
the above optimized conditions (Table 2). Among the screened
ligands, 1a resulted in high yield of the Chan–Lam coupling pro-
duct (entry 1). In the case of ligands 1b and 1c low yields were
observed even after longer reaction times (entries 2 and 3). The
reaction proceeds smoothly at 60 °C temperature, subsequently
we calculated the catalytic performance comparatively at low
and high temperatures. The isolated yield of the coupled product
was 86% at 80 °C temperature (entry 5). No coupling product was
observed at room temperature conditions (entry 6). We found that
10 mol % of Ni(OAc)2Á4H2O and 20 mol % of ligand 1a was sufficient
for the formation of diphenylamine product in high yield using
TMG base with toluene solvent at 60 °C.
The scope and feasibility of the above-mentioned optimized
reaction conditions applied to substituted anilines with different
arylboronic acids.20 The results are listed in Table 3. It is interesting
to observe that the reactions of para and meta substituted aryl-
boronic acid derivatives were easily performed with aniline and
produced the corresponding N-arylated products 4ab and 4ac in
74–80% yields (entries 2 and 3). The reaction of p-anisidine with
phenylboronic acid afforded the corresponding coupled product
4ad in moderate yield (entry 4). The coupled products of meta
substituted aniline 4ae–4ag were obtained in good yields (entries
5–7). The reaction of o-toluidine and 2-aminoacetophenone was
not influenced by the steric hindrance (entries 8–12). 2-bromoani-
line easily converted to 2-bromo-N-arylaniline (4am–4an) in
70–74% yield irrespective of the ortho bromide effect (entries 13
and 14). However the coupling reaction of 2-naphthylboronic acid
with aniline proceeded well with moderate yields of the corre-
sponding products (entry 15).
Further, we extended this optimized conditions to the coupling
reaction of arylboronic acids with a variety of cyclic secondary
amine derivatives (Table 4).20 N-Phenylpiperazine was effectively
converted to the coupled product in high yields (74–82%) with var-
ious boronic acids (entries 1–4), whereas the coupling reactions of
piperidine, morpholine, and pyrrolidine derivatives with 2-naph-
thylboronic acid requires a longer reaction time to complete the
reaction and produced the corresponding products in moderate
yields (entries 5–7). Furthermore, cyclohexylamine produced the
corresponding product in 70% yield with 2-naphthylboronic acid
(entry 8).
Upto to now, the mechanism of the Ni catalyzed Chan–Lam cou-
pling was not proposed. According to our study, there is not much
change observed in product formation when the reaction is con-
ducted either in the presence of air (Tables 1–4) or nitrogen atmo-
sphere (Table 2, entry 9). This indicates an oxidative process was
not involved in the formation of the product.12 The possible reso-
nance of TMG base in reaction between imine nitrogen and other
two nitrogen atoms at 1, 3 positions may well affect the boron
group of phenylboronic acid for efficient coupling with N-nucle-
ophile.21,22 No coupling product was observed with saturated
Table 4
Coupling reactions of 2-naphthylboronic acid with various N-nucleophilesa
1a
Ni(OAc)2 .4H2O/
TMG, toluene
Ar
R1RN H
B(OH)2
R1RN Ar
amine bases (Et3N and DABCO Table
1 entries 8 and 9).
Experiments related to this coupling are under progress in our
laboratory.
4ap-aw
2
3
Entry
1
RlRNH
Product
Yieldb (%)
82
Conclusions
Ph
Ph
Ph
N
N
N
NH
Ph
Ph
N
N
N
4ap
In summary, we have developed a new synthetic method for
nickel-catalyzed Chan–Lam cross-coupling reactions of various
amines and arylboronic acids. This method shows broad substrate
scope and produces all the corresponding coupling products in
moderate to good yields with low catalytic loadings. Further inves-
tigation into the use of other amine sources for above coupling
reaction is currently ongoing in our laboratory.
NH
NH
N
F
2
3
80
78
4aq
Cl
Ph
Ph
N
N
N
4ar
Ph
N
NH
Acknowledgments
N
4
5
6
7
74
4as
K.S. thanks the University Grants Commission (UGC), New Delhi
for Dr. D.S. Kothari research fellowship. Special thanks to professor
Samudranil Pal for the support.
NH
66c
62c
56c
N
4at
Supplementary data
O
NH
N
O
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2015.10.
047.
4au
NH
N
4av
H
N
References and notes
NH2
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a
Reaction conditions: 2-naphthylboronic acid (1 mmol), N-nucleophile
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20. General procedure for Chan–Lam cross-coupling reaction: The 25 mL RB flask was
charged with arylboronic acid (1 mmol), N-nucleophile (2 mmol), Ni
(OAc)2Á4H2O/1a (10 mol % of Ni(II) salt and 20 mol % of 1a), TMG (2 mmol),
and toluene (1 ml). The reaction mixture was stirred at 60 °C for 24 h. After
completion of the reaction, the reaction mixture was cooled to room
temperature, diluted with ethyl acetate (20 mL), and washed with brine
water. The combined organic phase was dried over anhydrous Na2SO4. After
removal of the solvent, the residue was subjected to column chromatography
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Please cite this article in press as: Keesara, S. Tetrahedron Lett. (2015), http://dx.doi.org/10.1016/j.tetlet.2015.10.047