Nickel-catalyzed denitrative etherification of activated nitrobenzenes

Article abstract of DOI:10.1007/s13738-018-1510-0

Electron-deficient nitrobenzenes were coupled with phenols/alcohols to form diaryl/alkyl aryl ethers by the aid of NiCl₂ as the catalyst. The reactions were conducted under ligand- and oxidant-free conditions without the exclusion of air or moisture. The initial studies upon the mechanism of the reaction revealed two solvent-dependent approaches. In molten TBAB, S_NAr mechanism seems to be predominated, while, in DMF, the reaction might include the radical species.

Full text of DOI:10.1007/s13738-018-1510-0

Journal of the Iranian Chemical Society
https://doi.org/10.1007/s13738-018-1510-0
ORIGINAL PAPER
Nickel-catalyzed denitrative etherification of activated nitrobenzenes
Fatemeh Zamiran1 · Arash Ghaderi1
Received: 3 July 2018 / Accepted: 24 September 2018
© Iranian Chemical Society 2018
Abstract
Electron-deficient nitrobenzenes were coupled with phenols/alcohols to form diaryl/alkyl aryl ethers by the aid of NiCl2 as
the catalyst. The reactions were conducted under ligand- and oxidant-free conditions without the exclusion of air or moisture.
The initial studies upon the mechanism of the reaction revealed two solvent-dependent approaches. In molten TBAB, SNAr
mechanism seems to be predominated, while, in DMF, the reaction might include the radical species.
Keywords Denitrative etherification · Cross coupling · Nickel · Nitrobenzenes · Green conditions
Introduction
investigation [9]. Biodegradation involving denitration by
nitrobenzene dioxygenase is an example of oxidative attack
to nitrobenzenes giving substituted catechols [10, 11]. Apart
from enzymatic reactions, the reaction of nitrobenzenes
with phenols has been reported for the synthesis of diaryl
ethers using palladium as the catalyst (Scheme 1, eq. 1) [12].
Synthesis of unsymmetrical diaryl ethers using ArB(OH)2/
H2O system was achieved under Rh catalysis (Scheme 1,
eq. 2) [13]. Nanoparticles of CuO were also found to be
effective catalyst for denitrative etherification of nitroben-
zenes using oxone as the source of oxygen (Scheme 1, eq. 3)
[14]. Thioetherification reaction of nitrobenzenes was also
reported using CuI as the catalyst giving the desired prod-
ucts in excellent yields (Scheme 1, eq. 4) [15]. Our group
has reported three-component thioetherification reactions
of nitrobenzenes using S8 as the sulfur source and copper
salts as the catalysts (Scheme 1, eq. 5) [16]. Palladacycle-
catalyzed synthesis of diaryl sulfones was reported from the
reaction of nitrobenzenes and sulfonates (Scheme 1, eq. 6)
[17]. Very recently, Nakao et al. reported an elegant work
for the synthesis of aromatic amines from the reaction of
nitrobenzenes with primary or secondary amines under pal-
ladium catalysis (Scheme 1, eq. 7) [18]. The same group
also reported the Suzuki-type reaction between nitroben-
zenes and aryl boronic acids (Scheme 1, eq. 8) [19]. This
was the first and only report for denitrative C–C bond for-
mation reaction.
Transition metal-catalyzed construction of aryl-oxygen
bonds is a topic of great importance in organic synthesis
[1–4]. Through these coupling reactions, a wide range of
aromatic ethers have been produced. Different synthetic
protocols have been reported using functionalized aromatic
compounds as one of the coupling partners and the meth-
ods are even extended to the total synthesis of biologically
active compounds [5]. Although some progresses have
been achieved in the synthesis of aromatic ethers starting
from aryl halides [6], replacement of other functionalities
in aryl moiety for these reactions is still challenging. As a
few example, the reaction of phenols/alcohols with aryltri-
fluoroborates has been reported to give diaryl or aryl alkyl
ethers using Cu(OAc)2·H2O/DMAP catalytic system under
open air [7].
Nitrobenzenes are among the most useful compounds
in organic synthesis which are involved in the synthesis of
different nitrogen-containing aromatics. These compounds
could be reduced easily to amines, azo compounds, oxi-
mes, etc. [8]. Nevertheless, reactions including denitra-
tion are still limited in the literature and need extensive
Electronic supplementary material The online version of this
article (https://doi.org/10.1007/s13738-018-1510-0) contains
supplementary material, which is available to authorized users.
Considering the above literature survey which also have
been summarized in Scheme 1, three transition metals (Cu,
Pd, and Rh) have been commonly used as the catalyst for
denitrative functionalization of nitrobenzenes. In addition,
* Arash Ghaderi
aghaderi@hormozgan.ac.ir
1
Department of Chemistry, College of Sciences, University
of Hormozgan, Bandar Abbas 71961, Iran
Vol.:(0123456789)
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Journal of the Iranian Chemical Society
OAr
Scheme 1 Different methods
for denitrative functionalization
of nitrobenzenes
R
Ar
OAr
P
R
d
-
c
A
R
a
r
t
B
a
l
(
y
2
O
z
H
e
d
(
)
e
q
)
.
2
8
.
)
q
e
(
Cu-catalyzed
OAr
Pd-catalyzed
R1R2NH
NR1R2
NO2
ArB(OH)2
(eq. 7)
(eq. 3)
R
R
R
C
u
-
c
a
t
2
A
a
l
r
y
S
)
z
H
6
e
d
(
.
e
q
q
e
(
.
4
)
O
O
SAr
S
Ar
R
R
SAr
R
there are only few other reports conducting the reaction under
metal-free conditions [20], Mg-promoted reactions [21], etc.
[22–25]. Interestingly, there is no report for Ni-catalyzed reac-
tions probably due to the known incompatibility of Ni toward
nitro compounds [1]. Hence, we were interested in filling
this space in the literature and applying nickel as the cata-
lyst for these cross-coupling reactions. In this article, we wish
to present our latest findings for denitrative etherification of
nitrobenzenes catalyzed by Ni(II) as an inexpensive and read-
ily available catalyst.
To this mixture, was added TBAB (1.5 g) and heated to
100 °C. Progress of the reaction was monitored by TLC.
After completion of the reaction, silica gel (1 g) was added
to the reaction vessel and the mixture was added to a col-
umn chromatography. Petroleum ether/ethylacetate (10:1)
was used as the eluent to separate the desired product.
Results and discussion
We have commenced our optimization studies employing
the reaction of p-nitrobenzaldehyde and phenol as the rep-
resentative reaction. Various parameters such as base, addi-
tive, solvent, and the amount of the catalyst (NiCl2) were
screened and the reaction temperature was set at 100 °C
(Table 1). The reaction was failed using NiCl2 (20 mol%)/
K2CO3 and dioxane as the solvent in 90 min reaction time
(Table 1, entry 1). Changing the solvent to DMSO gave only
8% of the desired product (Table 1, entry 2). Using the 1:1
mixture of DMSO/dioxane as the solvent resulted 28% iso-
lated yield of the desired product (Table 1, entry 3). The
yield of the product was improved by increasing the amount
of the catalyst to 40 mol% (Table 1, entry 4). Our studies
showed that toluene, water, and PEG were not suitable sol-
vents for this reaction (Table 1, entries 5–7). We have also
checked the reaction in DMF as the solvent under different
Experimental
General
All chemicals were purchased from Merck and Aldrich
chemical companies and used as received without further
purification. All experiments were run under air atmos-
phere unless stated otherwise. NMR data were determined
in Bruker instrument (500 MHz) using CDCl3 as the solvent.
General procedure for the etherification
of nitrobenzenes with phenols/alcohols
A vessel was charged with nitrobenzene (0.5 mmol), phenol/
alcohol (1 mmol), NiCl2 (0.1 mmol), and K3PO4 (2 mmol).
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Journal of the Iranian Chemical Society
Table 1 Optimization studies for the reaction of p-nitrobenzaldehyde and phenol
CHO
OH
CHO
NiCl2 (20 or 40 mol%)
+
base, additive,
O2N
O
solvent, 100 o
C
1a
2a
3a
Entry
Catalyst (mmol)
Base (mmol)
Additive
Solvent
Time (min)
Yield (%)
1
2
3
4
5
6
7
8
NiCl2 (0.1)
NiCl2 (0.1)
NiCl2 (0.1)
NiCl2 (0.2)
NiCl2 (0.1)
NiCl2 (0.1)
NiCl2 (0.1)
NiCl2 (0.1)
NiCl2 (0.1)
NiCl2 (0.1)
NiCl2 (0.1)
NiCl2 (0.2)
NiCl2 (0.1)
NiCl2 (0.1)
NiCl2 (0.1)
NiCl2 (0.2)
NiCl2 (0.2)
NiCl2 (0.2)
NiCl2 (0.2)
NiCl2 (0.2)
NiCl2 (0.2)
NiCl2 (0.2)
NiCl2 (0.2)
NiCl2 (0.2)
NiCl2 (0.1)
NiCl2 (0.2)
NiCl2 (0.1)
–
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
NaOH (1)
Cs2CO3 (1)
Cs2CO3 (2)
Cs2CO3 (1)
Cs2CO3 (1)
K3PO4 (1)
K3PO4 (2)
K3PO4 (2)
K3PO4 (2)
K3PO4 (2)
K3PO4 (2)
K3PO4 (2)
K3PO4 (2)
K3PO4 (2)
K3PO4 (2)
K3PO4 (2)
K3PO4 (2)
K3PO4 (2)
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
Dioxane
DMSO
DMSO/dioxane
DMSO/dioxane
Toluene
H2O
PEG200
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
90
90
90
90
90
90
90
90
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
240
240
240
240
30
–
8
28
40
–
–
Trace
18
17
20
30
30
20
24
31
–
9
10
11
12
13
14
15
16a
17
18
19
20
21
22
23
24
25
26
27
28
29
30a
1,10-Phen
DMEDA
Ethylacetoacetate
PPh3
Bipy
I2
Oxone
Bipy+oxone
–
–
–
–
–
–
–
–
–
26
38
33
39
47
68
58
–
DMF
DMF
DMF
TBAB
TBAB
TBAB
TBAB
DMF
K3PO4 (2)
K3PO4 (2)
K3PO4 (2)
7
–
–
–
NiCl2 (0.1)
TBAB
240
Reaction conditions: 4-nitrobenzaldehyde (0.5 mmol), phenol (1 mmol), NiCl2 (0.1 or 0.2 mmol), additive (0.2 mmol), solvent (3 mL), or TBAB
(1.5 g) at 100 °C
aH2O (1 mL) was added as the co-solvent
conditions (Table 1, entries 8–24). The reactions were failed
by adding H2O as the co-solvent or using 1,10-phenanthro-
line or DMEDA as the additives (Table 1, entries 16–18).
When using ethylacetoacetate as the additive, the –NO2
group was selectively reduced to –NH2 leaving the formyl
group intact (Table 1, entry 19). Under these conditions, the
desired coupling product was not detected by the GC–MS
analysis. However, under other employed conditions, the
favorite products were isolated in low-to-moderate yields
(Table 1, entries 20–24). Switching the solvent to molten
TBAB increased the yield of the reaction up to 68% in the
presence of K3PO4 as the base (Table 1, entry 25). Increas-
ing the amount of the catalyst to 40 mol% was not effective
and resulted a slight decrease in the yield of the product
(Table 1, entry 26). The reaction was failed in the absence
of the base and only 7% of the product was obtained when
the reaction was performed under catalyst-free conditions
(Table 1, entries 27, 28). The same catalyst-free reaction in
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Journal of the Iranian Chemical Society
DMF resulted no yield of the product (Table 1, entry 29).
The reaction was failed when water (1 mL) was added to the
reaction under the standard conditions (Table 1, entry 30).
Under the optimized conditions (Table 1, entry 25),
different nitrobenzenes (1) and phenols/alcohols (2) were
subjected to the cross-coupling reactions for the synthesis
of ethers (3) (Table 2). The reaction of p-nitrobenzaldehyde
(1a) with phenol (2a) was conducted under the standard
conditions giving the desired product (3a) in 68% isolated
yield (Table 2, entry 1). Phenol-bearing p-methoxy group
Table 2 Reaction of different nitrobenzenes with phenol derivatives
G
G
NiCl2 (20 mol%)
R2 OH
+
R2
K3PO4, TBAB
O2N
O
100 oC
1
2
3
Entry
Nitrobenzene
Phenols
Product
Time
Isolated
(min) yield (%)
CHO
OH
CHO
CHO
240
68
O2N
O2N
O
O
1
3a
1a
2a
CHO
CN
OH
MeO
2
240
240
270
270
74
86
40
35
MeO
2b
3b
1a
1b
1b
1b
OH
CN
3
4
5
2a
O2N
O
O
3c
CN
OH
2c
O2N
O2N
CN
3d
CN
OH
O
CN
O
2d
3e
3f
O
O
OH
6
7
240
240
78
57
2a
2b
O2N
O2N
O
1c
OH
O
MeO
MeO
O
3g
3h
3i
1c
1d
1d
NO2
NO2
OH
CHO
8
9
240
270
-
O
2a
CHO
OH
MeO
CHO
CN
14
MeO
O
2b
CHO
CN
10
11
12
1
1
1
77
33
OH
OH
O2N
O2N
O2N
O
O
O
2e
2f
3j
1b
1b
1b
CN
CN
CN
3k
CN
trace
OH
2g
3m
Reaction conditions, nitrobenzenes (0.5 mmol), phenols (1 mmol), NiCl2 (0.1 mmol), K3PO4 (2 mmol), TBAB (1.5 g) at 100 °C
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Journal of the Iranian Chemical Society
(2b) resulted in slightly higher yield of the product (3b)
(Table 2, entry 2). Using the same procedure, the reaction
of p-nitrobenzonitrile (1b) with phenol (2a) afforded the
corresponding product (3c) in 86% isolated yield (Table 2,
entry 3). The results demonstrated that steric hindrance on
nitrobenzenes or phenols has negative effects on the reac-
tion. The reaction of α-naphthol (2c) or β-naphthol (2d) with
p-nitrobenzonitrile (1b) gave moderated yields of the desired
products (Table 2, entries 4, 5). Under the standard condi-
tions, the reaction of o-nitrobenzaldehyde (1d) with phenol
(2a) failed probably due to the steric effects (Table 2, entry
8). Using p-methoxy phenol (2b) as a stronger nucleophile
in the same reaction gave the product (3i) in only 14% yield
(Table 2, entry 9). Isoamyl alcohol (2e) and n-butanol (2f)
were also checked in this reaction giving the corresponding
products in moderate-to-high yields (Table 2, entries 10,
11). The lower isolated product for entry 11 might be due
to the evaporation of n-butanol (2f) during the course of the
reaction. Only a trace amount of product was observed when
bulky t-butanol (2g) was employed (Table 2, entry 12).
To obtain some information about the mechanism of
the reaction, the following experiments were conducted.
In an experiment, the standard reaction (Table 1, entry
25) was carried out in the presence of TEMPO as a radi-
cal scavenger to check if the process includes a radical.
Analysis of the reaction mixture after 240 min revealed
that the reaction was not affected by TEMPO excluding
the radical involvement in this process. We assumed that,
when the reaction was conducted in molten TBAB, the
predominated mechanism to produce the desired product
is SNAr and NiCl2 acts as a Lewis acid facilitating the
pathway. When the reaction was conducted in the pres-
ence of AlCl3 as a strong Lewis acid instead of NiCl2, the
desired product was produced in 72% yield. This result
supports the SNAr mechanism. As previously mentioned,
the reaction in the absence of the catalyst, proceeded
poorly giving the desired product (3a) in only 7% yield
(Table 1, entry 28) [26]. Interestingly, when the same reac-
tion was performed in DMF (Table 1, entry 15), addition
of TEMPO hampers the reaction and no desired product
was produced. Instead, the starting material was converted
to a mixture of products. When switching the catalyst to
AlCl3, no desired product was obtained in DMF. This
observation shows the involvement of a different mecha-
nistically pathway. In this case, the involvement of Ni(III)-
ligand-radical species is possible [1, 27]. As mentioned
above, the reaction of 2-nitrobenzaldehyde with phenol
failed when TBAB was employed as the reaction medium
probably due to the steric hindrance in the intermediate
of SNAr mechanism (Table 2, entry 8). In another experi-
ment, this reaction was reinvestigated in DMF as the sol-
vent. Intriguingly, the desired product was obtained in 33%
yield (Scheme 2). This result agrees with our proposed
pathway, since there is relatively low steric hindrance in
the radical intermediate.
For comparison, we carried out the reaction of
p-fluorobenzaldehyde, which is known to be active
substrate in SNAr mechanism, with phenol in medium
of molten TBAB and in DMF (Scheme 3). The results
showed that 70–75% yield of the desired product was
obtained in both cases, indicating that the reaction involv-
ing nitrobenzenes does not progress via SNAr mechanism
when conducting in DMF, but, in molten TBAB, the reac-
tion proceeds via SNAr pathway.
By the aid of UV spectroscopy, Nowrouzi et al.
observed that Ni(II) converts into Ni(0) in TBAB medium
[28]. If the same effect operates in our system, we expect
that the oxidative addition mechanism would be possi-
ble in the presence of Ni(0). Hence, we have employed
nitrobenzene as the starting material and ran the reaction
Scheme 2 Effect of solvent on
CHO
CHO
the reaction
O
NO2
OH
NiCl2 (20 mol%)
+
K3PO4, 100 o
240 min
C
1d
2a
3h
Solvent
Yield
TBAB
DMF
0%
33%
F
Scheme 3 Reaction of
p-fluorobenzaldehyde with
phenol in DMF or TBAB as the
solvent
OH
O
NiCl2 (20 mol%)
+
K3PO4, 100 o
240 min
C
OHC
OHC
DMF or TBAB
1e
2a
3h
70-75%
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Journal of the Iranian Chemical Society
Ni(II)
TBAB
Ni(0)
Scheme 4 Our expectation if
Ni(0) is produced in situ from
Ni(II)/TBAB system
OH
NiII
O
NO2
NO2
24 h
Not formed
CHO
In another experiment, we have conducted the model reac-
tion in a mixture of TBAB and DMF as the medium. To our
surprise, the reaction was failed in DMF/TBAB solvent sys-
tem. This remains an open question for us to know the reason.
O2N
Ni(II)
Conclusion
O
O2N
In conclusion, we have developed the first Ni-catalyzed
etherification of nitrobenzenes by a simple and practical
approach. Denitrative etherification of phenols and alco-
hols was reported under ligand- and oxidant-free conditions.
Using this procedure, sensitive functional groups such as
formyl and nitrile groups are tolerated. Preliminary studies
on the mechanism of the reaction show that two different
approaches are involved depending on the reaction solvent
employed. When conducting the reaction in molten TBAB,
the reaction proceeds via SNAr mechanism, while, in DMF,
the Ni(III) ligand-radical species might be included as the
active intermediate.
Ni(II)
TBAB
K3PO4
RO
ROH
Ni(II)
O
RO
O2N
ROAr
NO2
+
Scheme 5 Plausible mechanisms for the reaction
Acknowledgements The authors are thankful to INSF (Grant num-
ber: 95825781) and University of Hormozgan research council for the
financial support.
under the standard conditions. No product was detected
after 24 h reaction time (Scheme 4). This result shows
that even if Ni(0) has been formed during the reactions
(Table 2), it would not affect the course of the reaction
and, in turn, oxidative addition/reductive elimination
mechanism can probably be excluded.
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have conducted the reaction using p-iodonitrobenzene.
Analysis of the reaction mixture shows that 4-nitrobiphe-
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