Copper-catalyzed regioselective synthesis of N-aryl amides from aldoximes and aryl halides

Article abstract of DOI:10.1002/ejoc.201301868

Ligand-assisted copper-catalyzed reaction of aldoximes with aryl halides is described for the regioselective synthesis of N-aryl amides. This protocol is simple and compatible with a wide range of functional groups attached to the aryl ring of the halides as well as aldoximes. Copyright

Full text of DOI:10.1002/ejoc.201301868

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201301868
Copper-Catalyzed Regioselective Synthesis of N-Aryl Amides from Aldoximes
and Aryl Halides
[a]
[a][‡]
and Dinesh Kumar Nayak[a][‡]
Niranjan Panda,* Raghavender Mothkuri,
Keywords: Homogeneous catalysis / Rearrangement / Copper / Aldoximes / Amides
Ligand-assisted copper-catalyzed reaction of aldoximes with
aryl halides is described for the regioselective synthesis of N-
aryl amides. This protocol is simple and compatible with a
wide range of functional groups attached to the aryl ring of
the halides as well as aldoximes.
II
Introduction
centration of a cheap Cu catalyst for the effective transfor-
[
16]
mation of aldoximes into primary amides. CuSO ·5H O-
mediated transformation of aldehydes into primary amides
in one-pot through an aldoxime intermediate was revealed
by Ganguly and his co-workers.
catalyzed direct transformation of oximes into N-substi-
tuted amides does not yet have precedent. Rather, a few
methods including the rearrangement of ketoximes into N-
aryl amides in the presence of some other transition metals
such as Rh and Hg have been reported. For example,
Yamaguchi and Arisawa described a Rh-catalyzed protocol
4
2
Carboxamides are pivotal building blocks in many phar-
maceuticals and biologically active natural products.
[
1]
Furthermore, they are potential precursors in organic syn-
thesis as well as major constituents of high-performance
[10]
However, the copper-
[
2]
materials. The classical method for amide synthesis in-
cludes the coupling of a carboxylic acid (by using coupling
reagents such as carbodiimide)[ with an amine; this pro-
cedure produces a stoichiometric amount of waste products
3]
[
4]
and thus innately faces serious environmental problems.
The rearrangement of ketoximes in the presence of acid,
known as the Beckmann rearrangement,[ often offers a
straightforward method for the formation of N-substituted
for the transformation of ketoximes into N-substituted
Acetonitrile-mediated HgCl -catalyzed conver-
sion of ketoximes into secondary amides/lactams was re-
5]
[17]
amides.
2
amides (R C=NOH Ǟ RCONHR). Nevertheless, the ne-
[18]
2
ported by Ramalingan and Park. Although, these results
cessity of high reaction temperatures and the use of large
amounts of strong Brønsted acids and dehydrating media
are promising, the use of toxic and precious catalysts im-
pedes the practicality of these approaches. Moreover, if
oximes of unsymmetrical ketones are used, the formation
of regioisomeric mixtures limits the scope of these reactions.
Hence, the development of efficient and less-expensive cata-
lytic systems (preferably by using low-costing Fe and/or Cu
catalysts) for the regioselective synthesis of amides from
oximes is deemed to be important.
Over the past decades, the ligand-assisted copper-cata-
lyzed N-arylation of amides with aryl halides has emerged
as a potential method for the construction of C–N bonds
Scheme 1, a). Furthermore, the reacting primary amides
can be obtained in an atom-economic fashion from the
[
6]
with the production of large amounts of byproducts are
the inevitable drawbacks of this reaction. Notably, the acid-
catalyzed Beckmann rearrangement of aldoximes, in gene-
ral, leads to nitriles,[ whereas the same substrate in the
presence of transition-metal catalysts leads to primary
7]
[
8]
amides. It has been hypothesized that the transition-
metal-catalyzed reactions proceed through a dehydration/
hydration sequence via the formation of a discrete nitrile
[
9,10]
intermediate.
metal (i.e., Rh,
Evidently, a number of precious transition
[19]
[
11]
[12]
[13]
[14]
[15]
Ru,
Ir,
Pd,
and Au/Ag ) cata-
(
lysts were successfully employed for the atom-efficient syn-
thesis of primary amides from aldoximes. Owing to their
economic attractiveness, the use of copper catalysts for such
transformations has drawn significant attention. For in-
stance, Williams and Ramón independently used a low con-
copper-catalyzed dehydration/hydration of aldoximes
[9,10]
(Scheme 1, b).
Stimulated by these facts, we anticipated
that copper-catalyzed rearrangement of aldoximes in the
presence of an aryl halide might lead directly to N-aryl
amides with alleviation of the regioselectivity problem that
is frequently associated with the Beckmann rearrangement.
For the first time, we report herein a ligand-assisted, cop-
per-catalyzed, regioselective, practical synthesis of N-aryl
amides from the reaction of aldoximes with aryl halides
(Scheme 1, c).
[
a] Department of Chemistry, National Institute of Technology,
Rourkela, Odisha 769008, India
E-mail: npanda@nitrkl.ac.in
https://sites.google.com/site/nitrklcynpanda/
[
‡] These authors contributed equally to this work.
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301868.
1602
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 1602–1605

Copper-Catalyzed Regioselective Synthesis of N-Aryl Amides
130 °C in the absence of any solvent also delivered 3a in
appreciable yield (62%) with decomposition of the remain-
ing starting materials.
Table 1. Optimization of the reaction conditions.[a]
Scheme 1. Approaches to N-aryl amides from aldoximes.
[c]
Results and Discussion
Entry Catalyst
Ligand[b]
–
1,10-phen Cs
2
1,10-phen K CO3 o-xylene
bipy
TMEDA
acac
EDA
DMEDA
DMEDA DBU
DMEDA Cs CO
3
DMEDA NaOAc o-xylene
DMEDA KOH
DMEDA PO
4
DMEDA K CO3 o-xylene
2
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
–
Base
Solvent
Yield [%]
1
2
3
4
5
6
7
8
9
CuI
CuI
CuSO ·5H O
Cs
2
2
CO
CO
3
toluene
o-xylene
0
We began our study with the reaction of iodobenzene
3
20
30
21
27
17
n.r.
82
n.r.
49
n.r.
28
37
21
52
61
32
70
48
0
(1a) and benzaldoxime (2a) as the model reaction. Upon
4
4
4
4
4
4
4
4
4
4
4
2
heating 1a and 2a at reflux in toluene in the presence of
CuSO
CuSO
CuSO
CuSO
CuSO
CuSO
CuSO
CuSO
CuSO
CuSO
·5H
·5H
·5H
·5H
·5H
·5H
·5H
·5H
·5H
·5H
2
O
O
O
O
O
O
O
O
O
O
K
K
2
K
2
K
2
2
CO
CO
CO
CO
CO
3
o-xylene
o-xylene
o-xylene
o-xylene
o-xylene
o-xylene
o-xylene
2
3
CuI and Cs CO , in line with the earlier report of Maitra
2
3
20]
[
2
3
and co-workers
on the copper-catalyzed O-arylation of
2
3
aldoximes with aryl iodides, the deoximation occurred with
the formation of contaminating benzaldehyde, and no trace
of benzanilide (3a) or the O-aryl oxime ether was obtained
2
K
2
3
2
1
0
2
2
1
1
2
(Table 1). However, upon the addition of 1,10-phenanthrol-
1
2
2
o-xylene
o-xylene
ine (1,10-phen, 30 mol-%) to the reaction mixture, 3a was
13
2
K
3
isolated in 20% yield with the decomposition of the remain- 14
ing aldoxime. This observation persuaded us to optimize 15
Cu(OAc)2
CuCl
CuO
2
K
2
CO
CO
CO
CO
CO
CO
CO
CO
CO
K CO3 o-xylene
3
DMF
DMF
16
K
2
K
2
3
the reaction conditions by identifying the best catalyst, li-
gand, base, solvent, and reaction temperature. Among the
various ligands examined, the use of N,NЈ-dimethylethyl-
1
18
7
CuBr
CuI
3
o-xylene
o-xylene
DMF
DMSO
toluene
K
2
K
2
3
1
9
CuCl
CuSO
CuSO
CuSO
–
3
enediamine (DMEDA) was the most effective to produce 20
4
·5H
4
·5H
4
·5H
2
O
O
O
K
2
K
2
3
2
1
2
3
53
3
a (Table 1, entry 8). The choice of base as well as its con-
centration was found to be crucial for this reaction. Among
the tested bases [Cs CO , tBuOK, K PO , KOH, NaOAc,
2
2
2
K
2
K
2
3
1,4-dioxane n.r.
o-xylene
23
3
n.r.
n.r.
n.r.
n.r.
2
3
3
4
24
4 2
CuSO ·5H O
2
K CO , 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), pyr- 25
idine] K CO (5 equiv.) furnished the best result (82% yield; 26
CuSO ·5H O
DMEDA
DMEDA
–
o-xylene
H O
2
2
3
4
2
4
CuSO ·5H
2
O
2
K CO
3
2
3
Table 1, entries 8–13), whereas a lower amount of K CO3 [a] Reaction conditions: A mixture of iodobenzene (100 mg),
2
(
2 equiv.) gave 3a in 47% yield over a period of 12 h. benzaldoxime (4 equiv.), copper catalyst (10 mol-%), ligand
(
30 mol-%), and base (5 equiv.) in solvent (1 mL) was heated at
30 °C for 12 h. [b] bipy = 2,2Ј-bipyridyl, TMEDA = N,N,NЈ,NЈ-
NaOAc, DBU, and pyridine did not furnish 3a. Likewise,
different copper catalysts were screened (Table 1, entries 8,
1
tetramethyl-1,2-ethylenediamine, acac = acetylacetonate, EDA =
ethylenediamine. [c] n.r.: no reaction.
1
4–19), and CuSO ·5H O (10 mol-%) and DMEDA
4 2
(
30 mol-%) in the presence K CO (5 equiv.) afforded the
2 3
optimum yield of 3a. Other catalysts such as CuCl , CuCl,
Treatment of the aldoxime under the optimum reaction
2
CuBr, Cu(OAc) , and CuO were less effective. The use of conditions in the absence of iodobenzene afforded both
2
CuI/DMEDA (Table 1, entry 18) gave a comparable result benzonitrile and benzamide (from TLC and GC). Notably,
I
II
(
70%), which demonstrates that both Cu and Cu catalyst under similar reaction conditions, if benzamide was taken
precursors are able to facilitate this transformation. instead of oxime 2, the N-aryl amide (e.g., 3a) was produced
II
Furthermore, it is possible that conversion between the Cu
in excellent yield (see the Supporting Information for de-
I
and Cu species might occur during this reaction process. tails), whereas a similar experiment with benznitrile did not
Upon performing the reaction at 130 °C in o-xylene, the furnish any anilide (from TLC). However, the addition of
optimum yield of 3a was obtained. However, lowering the water (1 equiv.) to the benznitrile produced N-aryl amide
temperature to 110 °C (at reflux in toluene) and increasing 3a, albeit in poor yield (20%). Reaction of benznitrile with
[
21]
the temperature to 140 °C (at reflux in o-xylene) furnished iodobenzene
under similar reaction conditions in the
3
a in 47 and 58% yield, respectively. If a similar reaction presence of 4-methoxybenzaldoxime (2b) afforded 3a along
[
20]
was performed in DMSO, the O-aryl oxime ether
re- with a small amount of 4. It was also observed that increas-
sulted without the formation of any trace of 3a (from TLC). ing the oxime concentration from 1 to 4 equiv. gave the best
Control experiments demonstrated that in the absence of yield of anilide, which indicated that the OH group of the
catalyst, base, or ligand, the amidation of iodobenzene did oxime was utilized in the hydrolysis. On the basis of these
not occur; rather, the starting material was recovered. Reac- observations and in line with earlier reports, it may be ex-
tion of 1a with 2a (4 equiv.) in the presence of CuSO ·5H O pected that the oxime initially transforms into the primary
4
2
[
10,16]
(
10 mol-%), DMEDA (30 mol-%), and K CO (5 equiv.) at amide,
which is subsequently N-arylated in one pot in
2
3
Eur. J. Org. Chem. 2014, 1602–1605
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1603

N. Panda, R. Mothkuri, D. K. Nayak
SHORT COMMUNICATION
the presence of CuSO ·5H O and a ligand (Scheme 1, Heteroaryl amides were also produced under the optimum
4
2
[
22]
a,b). Moreover, considering the catalytic behavior of the reaction conditions in appreciable yields (Table 2, entries 9
CuI/DMEDA complex to produce reasonable amounts of and 10).
3
a (Table 1, entry 18), an alternate plausible pathway may
Table 2. Reaction of aryl halides with aldoximes.
be proposed. We speculate that in the presence of a diamine
ligand, Cu quickly forms a complex, L Cu , that is sub-
II
II
2
sequently reduced in situ by the OH group of the oxime to
I [19b,23]
produce L Cu .
Oxidative addition of the aryl halide
2
I
to L Cu leads to complex A (Scheme 2). In the presence of
2
a nucleophile, the halide on the Cu center is exchanged to
[
9a,23b]
furnish B.
Then, reductive elimination produces inter-
mediate C, which undergoes hydrolysis by the oxime or the
[
10]
in situ generated H O to produce the N-aryl amide.
2
Scheme 2. Alternative pathway for the synthesis of N-aryl amides.
Having the optimal reaction conditions, we explored the
scope of the reaction with a variety of aryl halides. The
reaction of benzaldoxime (2a) with aryl iodides produced
N-aryl amides in good yields, whereas a similar reaction
with aryl bromides furnished 3a–g in moderate yields
(Scheme 3). This reaction protocol was found to be compat-
ible with electron-donating and electron-withdrawing sub-
stituents on the aryl bromides and iodides to produce the
corresponding N-aryl amides in moderate to good yields
(Scheme 3). Unfortunately, less-reactive aryl chlorides did
not couple with 2a under the optimum reaction conditions;
rather, the benzamide resulted instead.
Scheme 3. Reaction of aryl halides with benzaldoximes.
Conclusions
Next, the optimized protocol was applied to the coupling
In conclusion, we have developed a one-step protocol for
of substituted aryl aldoximes with iodobenzene (Table 2). the direct transformation of aldoximes into N-arylated
Pleasingly, the reaction furnished good results if aromatic amides in the presence of a copper catalyst. This reaction
aldoximes were used independent of the presence of elec- procedure is very simple and does not require any inert at-
tron-withdrawing or electron-donating groups with the alle- mosphere to afford good yields of the amides with complete
viation of the regioselectivity problem. Surprisingly, 4- alleviation of the regioselectivity problem that is frequently
hydroxybenzaldoxime did not react with iodobenzene to associated with the Beckmann rearrangement. Further in-
produce the corresponding anilide (Table 2, entry 5). vestigations on the application of this strategy for the syn-
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 1602–1605

Copper-Catalyzed Regioselective Synthesis of N-Aryl Amides
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Received: December 17, 2013
Published Online: February 7, 2014
Eur. J. Org. Chem. 2014, 1602–1605
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1605