Salen-Cu(II) complex catalysed N-arylation of pyrazole under mild conditions

Article abstract of DOI:10.3184/174751913X13795203316679

Three inexpensive and air-/moisture-stable complexes (Salden)Cu (Salden = N, N'-bis(salicylidene)-1,2-dimethylethylenediamine), (Saldch)Cu (Saldch = N, N'-bis(salicylidene)-1,2-cyclohexenediamine), and (Salph)Cu (salph = N, N'-bis(salicylidene)-1,2-phenylenediamine) were synthesised and evaluated as catalysts for the N-arylation of pyrazole with aryl halides. A variety of aryl iodides and bromides underwent coupling with pyrazole, promoted by the (Saldch)Cu complex, in moderate to excellent yields without the protection by an inert gas.

Full text of DOI:10.3184/174751913X13795203316679

636 RESEARCH PAPER
OCTOBER, 636–637
JOURNAL OF CHEMICAL RESEARCH 2013
Salen–Cu(II) complex catalysed N-arylation of pyrazole under mild
conditions
Yan Liu, Wei Liu, Qin Zhang, Ping Liu*, Jian-Wei Xie and Bin Dai
School of Chemistry and Chemical Engineering, the Key Laboratory for Green Processing of Chemical Engineering of Xinjiang Bingtuan, Shihezi
University, Shihezi City, 832004, P.R. China
Threeinexpensiveandair-/moisture-stablecomplexes(Salden)Cu(Salden=N,N′-bis(salicylidene)-1,2-dimethylethylenediamine),
(Saldch)Cu (Saldch=N, N′-bis(salicylidene)-1,2-cyclohexenediamine), and (Salph)Cu (salph=N, N′-bis(salicylidene)-1,2-
phenylenediamine) were synthesised and evaluated as catalysts for the N-arylation of pyrazole with aryl halides. A variety of
aryl iodides and bromides underwent coupling with pyrazole, promoted by the (Saldch)Cu complex, in moderate to excellent
yields without the protection by an inert gas.
Keywords: Salen–Cu complex, N-arylation; pyrazole, catalyse, C–N coupling
N-Aryl pyrazoles represent an interesting structural motif
that is frequently found in agrochemical and pharmaceutical
compounds.1 The development of convenient and efficient
methods for the synthesis of N-aryl pyrazoles has attracted
considerable attention. During the last few years, significant
efforts have been devoted towards developing convenient
approaches for the preparation of these compounds. Some
methods describing copper-catalysed coupling reactions using
various arylating reagents such as arylboronic acids and its
derivatives,2 aryllead triacetates,3 aryltrimethylstannanes,4
triarylbismuth diacetates5 or diaryliodonium salts6 have been
reported. However, these processes suffer from an intrinsic
limitation in terms of atom and step economy, because these
arylating reagents often require time-consuming multi-step
syntheses. As an alternative C−N bond-forming strategy,
the direct arylation of pyrazoles with aryl halides catalysed
by transition-metals represents a more efficient method
because they are straightforward and attractive.7 Despite these
significant advances, more efficient, air stable and cheaper
ligands or metal-complexes for facilitating these coupling
reactions under relatively milder conditions are still in demand.
Recently, we reported Suzuki–Miyaura reactions catalysed
by Salen and half-salen palladium(II) complexes.8 Although
Salen-Pd complexes showed low catalytic activity for C–C
coupling reactions, we assumed that Salen–Cu complexes might
be a class of effective catalysts for the C–N coupling reaction.
Recently, Zhou et al. have developed Salen–Cu complexes for
C–N coupling reaction of aryl halides with aqueous ammonia,
aliphatic amines and imidazoles.9–11 We now report Salen–
Cu complexes as catalysts for the N-arylation of pyrazole.
This system contains several advantages as following: (1)
the complexes were easily synthesised from cheap starting
materials, and stable in air and moisture; (2) the reaction
conditions were relatively mild and did not require protection
by an inert atmosphere; (3) the complexes worked well for aryl
iodides, and bromides with moderate to excellent yields.
Results and discussion
Synthesis of complexes 1–3
Complexes 1–3 were synthesised by the literature methods
(Fig. 1).12,13
Salen–Cu catalysed N-arylation reactions
Initially, the catalytic activity of the complexes 1–3 were
evaluated by coupling 4-iodotoluene with 1H-pyrazole as
a model reaction in the presence of NaOH at 100 °C for 12 h
in DMSO. As expected, the three Salen–Cu complexes all
exhibited good catalytic activity for this reaction, and gave
the desired product in 77–95% isolated yields (Table 1, entries
1–3). The coupling reaction did not occur in the absence of
any catalyst (Table 1, entry 4). Subsequently, we selected the
complex 2 as the catalyst to further investigate the effects
of other conditions on the N-arylation, including reaction
temperature, bases, solvents, and catalyst loading. The
results showed that lower temperature decelerated the rate
of the reaction. For example, 88% yield was obtained when
the reaction was carried out at 80 °C (Table 1, entry 5). Base
also played an important role in the catalyst systems. Among
the various bases examined, NaOH was the most effective,
although K3PO4, KOH and Cs2CO3 also promoted the coupling
Table 1 Optimisation of the reaction conditionsa
I
1-3
N
complex
N
HN
base solvent
,
temp, time
N
Me
Me
a
4
a
5
Entry
Complex
Base
Solvent
Temp/°C
Yield/%b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
1
2
3
–
2
2
2
2
2
2
2
2
2
2
NaOH
NaOH
NaOH
NaOH
NaOH
Na2CO3
K3PO4
Cs2CO3
Et3N
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
100
100
100
100
80
100
100
100
100
100
100
100
100
100
77
95
92
0
84
0
50
88
0
91
87
84
0
H
N
O
H
N
O
N
O
N
O
N
O
N
O
KOH
Cu
Cu
Cu
NaOH
NaOH
NaOH
NaOH
1
2
3
DMA
Toluene
DMSO
73c
Fig. 1 List of complexes 1–3.
aReaction conditions: 4-iodotoluene (0.5 mmol), 1H-pyrazole (1.0 mmol),
complexes 1–3 (10 mol%), base (1.0 mmol), and solvent (1 mL), reaction
time 12 h.
bIsolated yields.
cComplex 2 (5.0 mol%).
* Correspondent. E-mail: liuping1979112@yahoo.com.cn
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JOURNAL OF CHEMICAL RESEARCH 2013 637
reaction and gave the corresponding product in 50–91% yields
(Table 1, entries 7 and 8). However, Na2CO3 and organic base
NEt3 were ineffective (Table 1, entries 6 and 9). Consequently,
NaOH was used in the subsequent studies. Solvent was another
important factor affecting catalysis. It was found that DMSO
was the best solvent. Both DMF and DMA were not as good as
DMSO (Table 1, entries 11 and 12). Toluene was not suitable as a
solvent (Table 1, entry 13). Furthermore, decreasing the loading
of the complex 2 from 10 mol% to 5 mol% led to a decrease
in the yield (Table 1, entry 14). Finally, the combination of
Salen–Cu complex 2 (10 mol%), NaOH (2 equiv.) at 100 °C for
12 h in DMSO was chosen as the optimum conditions for the
N-arylation of 1H-pyrazole with 4-iodotoluene.
A range of substrates was then investigated with this catalytic
system under the optimum reaction conditions. As shown in
Table 2, most aryl iodides reacted with 1H-pyrazole smoothly
to afford the desired products in moderate to excellent yields.
Electronic effects seemed to have significant impact on the
reaction. For example, aryl iodides with electron-donating
substituents were be coupled with 1H-pyrazole to give the
products in 88–93% yields (Table 2, entries 2 and 3), whilst
aryl iodides with electron-withdrawing substituents including,
1-chloro-4-iodobenzene, 1-fluoro-4-iodobenzene, 1-bromo-
4-iodobenzene and 1-iodo-4-nitrobenzene also afforded the
corresponding arylated products in 75–87% yields (Table 2,
entries 7, 9–11). However, when 1-(4-iodophenyl)ethanone
and 4-iodophenol were used as coupling partners, the yields
dropped to 21% and 39% respectively (Table 2, entries 6 and
13). Unfortunately, with 4-iodobenzonitrile as the substrate, the
N-arylation reaction did not proceed smoothly (Table 2, entry
12). However, sterically demanding ortho substituents such as
1-iodo-2-methylbenzene and 1-iodo-2-methoxybenzene did not
hamper the arylation reaction and gave 82% and 83% yields
respectively (Table 2, entries 4 and 5). Next, we considered
the possibility of using aryl bromides as coupling partners.
However, low yields were obtained under the previously
optimised reaction conditions (Table 2, entries 14 and 15).
The system is effective in the coupling of 1H-pyrazole with
ArX (X=I, Br) to give moderate to excellent yields. The
easily availability of the catalyst, mild reaction conditions,
experimental simplicity, and broad substrate scope are features
of the catalytic method presented in the current paper. Further
application of these copper(II) complexes catalysed organic
reaction is currently on-going in our laboratory.
Experimental
All reactions were carried out under air using magnetic stirring unless
otherwise noted. 1H NMR spectra were recorded on a Bruker DPX-400
spectrometers using TMS as internal standard and CDCl3 as solvent.
EI–Mass spectra were measured on a LC/Q–TOF MS (Micromass,
England). All other reagents were of commercial analytical grade
quality.
N-Arylation of 1H-pyrazole; general procedure
Complex 2 (0.05 mmol) was added to a 5 mL of a sealed tube
containing the aryl iodide or bromide (0.5 mmol), 1H-pyrazole
(0.75 mmol), NaOH (1 mmol), and DMSO (1 mL). The mixture was
stirred at 100 °C for 12 h. After being cooled to room temperature,
the mixture was quenched with 10 mL H2O and extracted with EtOAc
(3×20 mL). The combined EtOAc extracts were dried with anhydrous
Na2SO4, filtered and the solvent was removed under reduced pressure.
The residue was purified by flash column chromatography on silica
gel with PE/EtOAc (from 10:1 to 5:1) as the eluent to afford the pure
products. All N-aryl pyrazoles reported here are known products and
were characterised by 1H NMR, and GC-MS.
We gratefully acknowledge financial support by the
National Basic Research Program of China (973 Program:
2012CB722603), the NSFC (No. 21103114), the Ministry
of Education Innovation Team (No. IRT1161), and Start-
Up Foundation for Young Scientists of Shihezi University
(RCZX201012, RCZX201014, RCZX201015).
Received 6 July 2013; accepted 6 August 2013
Paper 1302046 doi: 10.3184/174751913X13795203316679
Published online: 7 October 2013
Conclusions
In summary, we have developed a novel general catalytic
method for N-arylation of 1H-pyrazole promoted by complex 2.
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