Nickel-catalyzed reductive amidation of aryl-triazine ethers

Article abstract of DOI:10.1039/c9cc08727c

The reaction of activated phenolic compounds, 2,4,6-triaryloxy-1,3,5-triazine (aryl-triazine ethers), with various isocyanates or carbodiimides in the presence of a nickel pre-catalyst resulted in the synthesis of aryl amides in good to excellent yields.

Full text of DOI:10.1039/c9cc08727c

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Nickel-catalyzed Reductive Amidation of Aryl-triazine Ethers
Majid M. Heravi,*,a Farhad Panahi*,a,b and Nasser Iranpoorb
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
The reaction of activated phenolic compounds, 2,4,6-triaryloxy- methods often suffer from main drawbacks mainly, the use of
1,3,5-triazine (aryl-triazine ethers) with various isocyanates or harsh reaction conditions, tedious workup procedures as well
carbodiimides in the presence of a nickel pre-catalyst resulted in as showing limited scope.4 Furthermore, these classical
the synthesis of aryl amides in good to excellent yields.
methods are unfavourable in viewpoint of environmental
because of low atom efficiency and production of huge
amounts of waste products.5 To overcome these problems,
opening the new and efficient gate ways of new and efficient
synthetic approaches are still in much demands.6
Since an amidic bond as an ubiquitous functionality is
extensively found in great number of pharmaceuticals, natural
products, biologically active compounds and advanced
materials, it has attracted much interest of synthetic organic
chemists, worldwide.1 To express the invaluably of this bond, it
is enough to point out the chemical structure of peptides and
proteins, as well as number of privileged and prescribed drugs
containing amidic bond.2 Benzamide subunits are among the
most important building block in the structure of many
biological important compounds. The chemical structures of
some biologically important compounds containing benzamide
group are illustrated in Figure 1.3
One of the most practical, atom economic and efficient
synthetic methods to obtain benzamides is based on the use of
isocyanates through transition metal catalysis.7-9 In such
approaches, aryl halides are used as starting materials for the
synthesis of benzamides via the reaction of appropriate
organometallic reagents (such as Li, MgX, BR2, SnR3) with
isocyanate in the presence of a transition metal catalyst
(Scheme 1, a).7
a
Metal-catalyzed amidation of aryl halides with isocyanates
Ph
O
H
R
NCO
Catalyst: Pd, Rh, Ni
M = MgX, Li, BR2, SnR3
O
N
Ar
X
Ar M
(ref. 7)
(ref. 8)
H2N
CONHR
Ar
N
O
HN
N
O
OMe
HN
Ph
X = Br, I
anticonvulsant activity
O
anti-inflammatory activity
analgesic activity
DG
CONHR
N
DG
R
NCO
OMe
NH
N
H
N
N
H
N
N
O
Catalyst: Rh, Ru,
MeO
H
MeO
O
Br
MeO
NH
Cl
N
b
O
Metal-catalyzed amidation of aryl C-O electrophiles with isocyanates
N
H
previous work:
serotonin (5-HT) activity
antitumor activity
antiemetic agent
R
NCO
Figure 1. The chemical structure of some biologically active
molecules containing benzamide moiety
Ar OPiv
Ar OTs
(ref. 9)
CONHR
Ar
Ar OH
[Ni]
this work:
To synthesize benzamide derivatives especially those
which are known as prescribed drugs, the facile traditional
methods are commonly used. They are based on the
condensation of benzoic acid derivatives with amines. These
OAr
R
NCO
[Ni]
N
N
Ar OH
CONHR
Ar
ArO
N
OAr
aryl-azine ethers
a.Department of Chemistry, School of Science, Alzahra University, Vanak, Tehran,
Iran.
Scheme 1. Metal-catalyzed amidation reaction for synthesis of
amides using isocyanates
b.Chemistry Department, College of Sciences, Shiraz University, Shiraz 71454, Iran.
Electronic Supplementary Information (ESI) available: Experimental procedures,
spectral data and copy of 1HNMR and 13CNMR of synthesized compounds. See
DOI: 10.1039/x0xx00000x
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Carbon−hydrogen functionalization of aryl rings containing 20
Journal Name
none
dppf (20)
none
90
90
90
0
ortho-directing groups with isocyanates in the presence of a Rh
or Ru catalyst system can also give raise to benzamides.8
Another substance which can be used instead of aryl halides in
reaction with isocyanates is activated phenolic compounds as
the reactive aryl C-O electrophiles. In spite of such importance,
literature survey showed only a single report dealing with the
direct conversion of aryl C-O electrophiles to benzamides
(Scheme 1, b).9 However, C−O electrophiles have emerged as
prevailing and environmentally friendly alternatives for being
used instead of aryl halides.10
21
NiCl2.dmg (10)
NiCl2.dmg (10)
27
54
22
bipy (20)
a Reaction conditions: 1a (0.2 mmol), 2a (1.0 mmol), catalyst (x mol%),
ligand (x or 2x mol %), Zn (1.2 mmol), K2HPO4 (1.2 mmol), dry solvent
b
c
(2 mL) and under inert gas conditions. Isolated yields. DMA was
d
e
used as solvent. Dioxane was used as solvent. Mn was used as
f
g
reducing agent. 2.0 mmol of cyclohexyl isocyanate was used. no
reducing agent was used. h 0.6 mmol Zn was used.
The reaction between 2,4,6-triphenoxy-1,3,5-triazine (1a
)
and
cyclohexyl isocyanate afforded to the N-
Herein, we wish to report that the reaction of activated
phenolic compounds with cyanuric chloride (aryl-triazine
ethers)11 and isocyanates in the presence of a nickel catalyst
system could afford a wide range of benzamide derivatives
(Scheme 1). Noticeably, literature survey showed no report on
the Ni-catalyzed reductive amidation12 of aryl-triazine ethers
with isocyanates. This new synthetic method is highlighted by
its broad scope and good chemoselectivity profile for phenolic
compounds, as well as challenging substrate. The use of readily
available and air-stable aryl electrophiles in this coupling
reaction also makes the practicality of this method more
smoothly.
cyclohexylbenzamide (3a) in 55% isolated yield in the presence
of NiCl2.6H2O as catalyst and dppf as ligand at 80 °C (Table 1,
entry 1). The reaction yield was increased to 67% by use of
NiCl2(dppf) as nickel source (Table 1, entry 2). Then, we
checked different Ni pre-catalysts and NiCl2.dmg showed
superior activity and 90% of the desired product was isolated
from the reaction mixture (Table 1, entries 3-6). Beside of
NiCl2.dmg, other ligands were tested and dppf found being the
ligand of choice (Table 1, entries 7 & 8).
We found out that by increasing the reaction temperature
the yields were not changed remarkably and at room
temperature no product was observed (Table 1, entries 9-11).
The catalyst loading was optimized and 10 mol% of catalyst
was recognized as optimum amount (Table 1, entries 12 & 13).
By use of other solvents no improvement in the reaction yield
and conditions was observed, thus, DMF was used as the
solvent of choice (Table 1, entries 14&15). It was also found
that zinc is the better reducing agent in this reaction and no
We set out the optimization study using the reaction of
2,4,6-triphenoxy-1,3,5-triazine (1a) and cyclohexyl isocyanate
(2a) in the presence of a nickel catalyst system (Table 1).
Table 1. Optimization study of the amidation of aryl-azine
ethers in the presence of a Ni catalyst
increasing in the reaction yield was observed when
2
equivalents of cyclohexyl isocyanate was used (Table 1, entries
16 & 17). In the absence of reducing agent the reaction yield
was decreased remarkably and also by decreasing of its
amount, demonstrating key role of reducing agent in this
process (Table 1, entries 18 & 19). It should be noted that in
the absence of Ni catalyst source no product observed (Table
1, entry 20). Also the reaction yield was decreased to 27%
without using ligand (Table 1, entry 20). The reaction yield for
bipy as a nitrogen-based ligand was decreased to 54%,
therefore this type of ligands are not effective than phosphin
ligands in this reaction. In this way the entry 9 of Table 1 was
selected as a model reaction to secure the optimized reaction
conditions for this protocol.
With optimized reaction conditions in hand, the scope of
substrates tolerated in the reaction was investigated. To
explore the substrate scope and establishing the generality of
the new method, differently substituted phenols were also
successfully converted to their benzamides using isocyanates
(Scheme 2).
entry catalyst (mol %)
ligand (mol %)
temp (°C) yield (%)b
1
NiCl2.6H2O (10)
NiCl2(dppf) (10)
NiCl2(dppe) (10)
NiCl2(PCy3)2 (10)
NiCl2.dmg (10)
NiCl2.glyme (10)
NiCl2.dmg (10)
NiCl2.dmg (10)
NiCl2.dmg (10)
NiCl2.dmg (10)
NiCl2.dmg (10)
NiCl2.dmg (8)
dppf (20)
dppf (10)
dppf (10)
dppf (10)
dppf (20)
dppf (20)
dcype (20)
dppe (20)
dppf (20)
dppf (20)
dppf (20)
dppf (16)
dppf (24)
dppf (20)
dppf (20)
dppf (20)
dppf (20)
dppf (20)
dppf (20)
80
80
80
80
80
80
80
80
90
100
rt
55
67
35
72
90
77
90
80
92
88
0
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
90
90
90
90
90
90
90
90
88
92
85c
51d
83e
92f
11g
56h
As shown in Scheme 2, amide bond formation happens
under optimized reaction conditions with a range of phenolic
and isocyanate substrates. The reaction tolerates a wide
variety of functional groups, including -Me (3c-e, 3ab), -NO2
NiCl2.dmg (12)
NiCl2.dmg (10)
NiCl2.dmg (10)
NiCl2.dmg (10)
NiCl2.dmg (10)
NiCl2.dmg (10)
NiCl2.dmg (10)
(
3l-n,v,w), -Cl (3i-k,x), -F (3o-r), -CF3 (3s,t), and –NMe2 (3u,ad)
(Scheme 2). Both electron-poor and electron-rich phenols are
worked well with this procedure. A chemoselectivity was
observed between C−O and C−Cl bond cleavage and
2 | J. Name., 2012, 00, 1-3
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(1.0 mmol), catalyst (10.0 mol%), ligand (20.0 mol %), Zn (1.2 mmol),
K2HPO4 (1.2 mmol), dry DMF (2 mL) and under inert gas conditions.
Yields correspond to isolated products.
compounds 3i-k were synthesized successfully. Activated 2-
naphthol was subjected to the Ni-catalyzed amidation and
corresponding benzamides 3f-h and 3ac in high yields. 2,4-
Dichlorophenol as a sterically hindered substrate gave the
desired product (3x) in moderate yield. Heterocyclic substrates
including thiophene and pyridine can be employed in this
b
The reaction yields for aryl isocyanates using this
methodology were low (3ad) and this refer to the formation of
isocyanurates via trimerization of the aryl isocyanate in the
presence of a zerovalent metal Zn or Ni.13 In order to obtain
these compounds in high yields we used their corresponding
carbodiimides based on the previous report.14 Interestingly,
this procedure also worked well with carbodiimides as an
amidating agent (Scheme 3, compounds 3ad-af). Also, this
procedure works well with aliphatic carbodiimides to produce
corresponding amides in good yields (Scheme 3, compounds
protocol and amide products
(3y-ab) were obtained in
satisfactory yields. In the case of 2-pyridyl substrate low yield
of product was observed. Other commercially available
isocyanates including tert-butyl-, n-pentyl- and benzyl
isocyanates, were fruitfully converted to the amide derivatives
using this procedure. The synthetic usefulness of this
methodology in organic synthesis was further highlighted
using successful synthesis of a steroid estrone amide derivative
using tert-butyl isocyanate under our optimized condition
3b,k,l).
(3ab).
Scheme 3. Nickel-catalyzed synthesis of benzamides using
carbodiimides. Reaction conditions:
1 (0.2 mmol), 2 (1.0 mmol),
catalyst (10.0 mol%), ligand (20.0 mol %), Zn (1.2 mmol), K2HPO4 (1.2
b
mmol), dry DMF (2 mL) and under inert gas conditions. Yields
correspond to isolated products.
This protocol was also checked with other aryl-azine
ethers and results show that the numbers of nitrogen in the
azine ring and also position of nitrogen related to C-O bond are
two important factors in the reaction outcome (Scheme 4).
Scheme 4. Nickel-catalyzed synthesis of benzamides using
different aryl-azine ethers. Reaction conditions: aryl-azine ether
(0.6 mmol per aryl ring), isocyanatocyclohexane (1.0 mmol), catalyst
(10.0 mol%), ligand (20.0 mol %), Zn (1.2 mmol), K2HPO4 (1.2 mmol),
dry DMF (2 mL) and under inert gas conditions. b Yields correspond to
isolated products.
We proposed
a reaction pathway for Ni-catalyzed
amidation of activated phenolic compounds by isocyanates
based on the literature (Scheme 5).15
Scheme 2. Products of Ni-catalyzed reductive amidation of activated
phenols with cyanuric chloride. Reaction conditions:
1 (0.2 mmol), 2
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Journal Name
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As shown in Scheme 5, oxidative addition of aryl C-O
electrophiles to Ni(0) complex led to the formation of
intermediate
isocyanate with Ni complex
I
. Intermediate II is formed through interaction of
. This mechanism may be
I
D. G. Brown and J. Boström, J. Med. Chem. 2016, 59
,
involving a Zn-mediated reduction of the Ni(II) to generate a
Ni(I) species to produce intermediate II. Isocyanate can
coordinate with intermediate II to form intermediate III. In
intermediate III, aryl ring added to carbon of isocyanate group
4443−4458.
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Scheme 5. Proposed mechanism for nickel-catalyzed synthesis
of benzamides using aryl-azine ethers
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In summary, we have developed a novel and efficient
methodology for the conversion of phenolic compounds to
their corresponding benzamides. The reaction proceeds with a
catalytic amount of Ni under mild conditions. This procedure is
characterized by its operational simplicity and the ready
availability of the substrates employed. This approach also
established a new choice for the synthesis of amides using
isocyanates as amidating agent without the need for the
Heravi, F. Panahi, and N. Iranpoor, Org. Lett., 2018, 20
,
2753–2756. d) L. Wang, Y. Wang, J. Shen, Q. Chen and
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12 Some example of nickel catalyzed reductive
preparation
of
sensitive
organometallic
reagents.
Carbodiimides could be used instead of aryl isocyanates to
resolve the trimerization problem associated with them in the
presence of zerovalent metal Zn or Ni.
We are thankful to the Iran Science Elites Federation for
their financial support. Also, financial support from the
research councils of Alzahra University and Shiraz University
are acknowledged.
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Conflicts of interest
There are no conflicts to declare.
15 E. Serrano and R. Martin, Angew. Chem. Int. Ed. 2016,
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Notes and references
4 | J. Name., 2012, 00, 1-3
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