Iron complex-catalyzed N-arylation of pyrazoles under aqueous medium

Article abstract of DOI:10.1016/j.tetlet.2009.08.018

Commercially available FeCl₃·6H₂O with conformationally rigid diamine ligand is a highly effective catalyst for N-arylation of pyrazoles using aryl and heteroaryl iodides. It is notable to show that this complex is tolerable under aqueous medium and particularly the whole reaction utilizes water as the sole solvent without any additional organic co-solvents and surfactants. Attempted study using other nitrogen nucleophiles is described. This newly developed system provides an alternative protocol to Cu- and Pd-catalyzed N-arylation reactions.

Full text of DOI:10.1016/j.tetlet.2009.08.018

Tetrahedron Letters 50 (2009) 5868–5871
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Iron complex-catalyzed N-arylation of pyrazoles under aqueous medium
*
Hang Wai Lee, Albert S. C. Chan, Fuk Yee Kwong
Open Laboratory of Chirotechnology of the Institute of Molecular Technology for Drug Discovery and Synthesis, Department of Applied Biology and Chemical Technology,
The Hong Kong Polytechnic University, Hong Kong
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 6 July 2009
Revised 7 August 2009
Accepted 11 August 2009
Available online 14 August 2009
Commercially available FeCl3Á6H2O with conformationally rigid diamine ligand is a highly effective cat-
alyst for N-arylation of pyrazoles using aryl and heteroaryl iodides. It is notable to show that this complex
is tolerable under aqueous medium and particularly the whole reaction utilizes water as the sole solvent
without any additional organic co-solvents and surfactants. Attempted study using other nitrogen nucle-
ophiles is described. This newly developed system provides an alternative protocol to Cu- and Pd-cata-
lyzed N-arylation reactions.
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
lid inorganic base/liquid organic reagents contact under
solventless conditions. Herein, we disclose our results in Fe-cata-
Transition metal-catalyzed cross-coupling methodologies are
important in the application of structurally diversified small mole-
cule synthesis.1 These catalytic protocols can be utilized practically
in preparing pharmaceutically useful intermediate.2 In general,
palladium complexes3 have been found superior in these processes
and copper complexes4 also exhibit high efficiency in related pro-
tocols. Recently, Bolm5 and others6 reported that Fe complexes
were capable in catalyzing carbon–carbon and carbon-heteroatom
bond forming reactions.7 These notable advancements have been
identified as a new area of cross-coupling technology8 carried out
under relatively mild reaction conditions.
There has been considerable interest in recent years in the
study of solvent-free reactions. The catalytic organic transforma-
tion using solventless medium is particularly desirable because
of the environmental concerns.9 Solvent-free reactions sometimes
additionally offer higher reaction rate presumably due to more
concentrated reaction medium.10 Inspired by this advantage and
our continuous interests in cross-coupling reactions,11 we applied
solventless conditions for Fe-catalyzed cross-coupling reactions.
However, our initial study showed that there was exceeding diffi-
culty for agitation in the absence of solvent. This problem may
arise due to the excess of solid base. To overcome this problematic
issue, we turned our prototypical study using water to dissolve the
inorganic base and thus focused on the feasibility of Fe-catalyzed
cross-coupling under aqueous conditions.12,13 Under this at-
tempted investigation, we expect that the organic reagent droplets
are suspended and surrounded by the aqueous alkaline medium,
thus efficiently providing additional surface area of contact for re-
agents. In fact, this is a preferable reaction medium than just in so-
lyzed N-arylation of pyrazoles using water as the reaction med-
ium.14 This catalytic system is highly attractive which comprises
economical FeCl3Á6H2O with commercially available diamine
ligand.
In our initial study, we found that the solventless conditions
obviously suffering from difficult agitation gave only 22% yield of
the desired product (Table 1, entry 1). Gratifyingly, by employing
water to dissolve the inorganic base, a much higher product yield
was obtained (entry 2). These results provided important ground
work for our further investigations. A survey of commercially avail-
able diamine ligands showed that L1 is the most suitable ligand
while L2 and L4 provided slightly lower yields (entries 2, 3, and
5). TMEDA and 1,10-phenathroline were found to be inferior (en-
tries 4 and 6). Picolinic acid, which we demonstrated as highly ac-
tive at room temperature in Cu-catalyzed C–C bond coupling
reaction,15 gave only a trace amount of the desired product in
the Fe-catalyzed N-arylation of pyrazole (entry 7). Control experi-
ment showed that no N-arylated pyrazole was afforded in the ab-
sence of ligand as judged by GC–MS analysis (entry 8). Commonly
used bases, such as K3PO4 and K2CO3 gave good yields of product
while NaOt-Bu provided poor conversion (entries 9–11). Increasing
the amount of either FeCl3Á6H2O or L1 showed slight improve-
ments on the product yield (entries 12 and 13). Interestingly, we
found the concentration of base in the reaction medium also affect-
ing the aryl iodide conversion. Concentration of base from 2 M to
4 M was the best range for this reaction (entries 14–16).
To probe the efficiency of this aqueous catalytic system, a range
of aryl iodides were examined (Table 2). Substituted group with
different electronic properties on the electrophile gave good to
excellent yield of the corresponding products (entries 1–6). Partic-
ularly noteworthy was that free –NH2 group was tolerable under
these reaction conditions (entry 7). 3-Iodobenzyl alcohol was a
* Corresponding author.
E-mail address: bcfyk@inet.polyu.edu.hk (F.Y. Kwong).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.08.018

H. W. Lee et al. / Tetrahedron Letters 50 (2009) 5868–5871
5869
Table 1
Initial screenings on the feasibility of aqueous Fe-catalyzed N-arylation of pyrazolea
Me
Me
Me
10 mol% FeCl3•6H2O
20 mol% L
N
HN
N
base, water
N
Me
I
135 °C
MeHN
NHMe
NMe2
O
L2
L3
N
OH
N
N
H2N
NH2
MeHN
NHMe
Me2N
L1
L4
L5
L6
Entry
Base
Ligand L
Solvent
%Yieldb
1
2
3
4
5
6
7
8
9
10
11
12c
13d
14
15
16
K3PO4ÁH2O
K3PO4ÁH2O
K3PO4ÁH2O
K3PO4ÁH2O
K3PO4ÁH2O
K3PO4ÁH2O
K3PO4ÁH2O
K3PO4ÁH2O
K3PO4
L1
L1
L2
L3
L4
L5
L6
No solvent
Water
Water
Water
Water
Water
Water
Water
Water
22
74
70
<1
69
<1
<1
0
74
72
23
80
77
75
70
27
No ligand
L1
L1
L1
L1
L1
L1
L1
L1
K2CO3
NaOt-Bu
Water
Water
Water
Water
K3PO4ÁH2O
K3PO4ÁH2O
K3PO4ÁH2O
K3PO4ÁH2O
K3PO4ÁH2O
Water (4 M)e
Water (2 M)e
Water (1 M)e
a
b
c
Reaction conditions: aryl iodide (1.5 mmol), pyrazole (1.0 mmol), FeCl3Á6H2O (0.1 mmol), ligand L (0.2 mmol), solvent (0.5 mL), and base (2.0 mmol) under N2 for 24 h.
Isolated yields.
20 mol % FeCl3Á6H2O and 40 mol % L1 were used.
d
e
40 mol % L1 was used.
Molarity of base (4 M = 0.5 mL water; 2 M = 1.0 mL water; 1 M = 2.0 mL water).
feasible coupling partner in this catalysis (entry 10). Sterically hin-
dered 2-iodotoluene provided good yield of the desired product
(entry 11).
under these reaction conditions. Notably, we have successfully
showed the first examples of heteroaromatics in this type of Fe-
catalyzed pyrazole arylation. This new system is believed to have
potential of being an alternative protocol for accessing a variety
of N-arylated pyrazoles and their derivatives.
It is of high challenge to use heteroaryl substrate in the cross-
coupling reaction as the heteroatom usually renders the transition
metal complex coordinatively saturated, and thus retarded the rate
of reaction. Upon applying the FeCl3Á6H2O/L1 catalyst system, the
heteroaryl substrates were efficiently transformed to the corre-
sponding product in good yields (Table 3). Nitrogen-containing
heterocycles provided slightly better yield than sulfur-containing
heterocycles (Table 3, entries 1–4). These results represent the first
examples of heteroarylation in Fe-catalyzed pyrazole arylation.
In order to further explore the substrate scope, we attempted to
investigate other nitrogen nucleophiles (Table 4). Intriguingly, sim-
ilar structures of indole and azaindole showed significantly differ-
ent reactivity in the arylation reaction, and the azaindole furnished
the desired product in 87% yield. Sterically congested carbazole
afforded the product in low yield. Substituted pyrazole derivatives,
indazole and 3,5-dimethylpyrazole gave moderate yield of the cor-
responding products.
In addition to the heterocycles that have one or two nitrogen
atoms, we also tried the cross-coupling of triazoles. Moderate yield
was obtained when 1,2,4-triazole was coupled with 2-iodopiperi-
zine (Scheme 1).
In conclusion, we have established an effective and economical
catalyst system, FeCl3Á6H2O/L1, for N-arylation of pyrazoles and
their derivatives. This catalytic system has beneficial feature of
using aqueous base as the reaction medium. Aromatic amino group
and benzyl alcohol moiety on electrophilic partners are compatible
2. Experimental section
2.1. General considerations
Unless otherwise noted, all reagents were purchased from com-
mercial suppliers and used without purification. DMF was pre-
dried by calcium hydride and distillated under reduced pressure.
Toluene was distilled from sodium benzophenone ketyl under
nitrogen. Commercially available aryl iodides (liquid form only)
were purified by passing through a short plug (0.5 cm wide  4 cm
height) of neutral alumina or distillation under reduced pressure.
GC analysis was conducted on a HP G1800C GCD system using a
HP5MS column (30 m  0.25 mm). Known products were charac-
terized by NMR and mass spectroscopy and compared to the liter-
ature data or to those of authentic sample analysis.
General procedures. FeCl3Á6H2O (0.1 mmol), L1 (0.2 mmol), ArI
(1.5 mmol, if solid), pyrazole (1.0 mmol), and K3PO4ÁH2O
(2.0 mmol) were charged to a Teflon screw-capped Schlenk tube
(approx. 10 mL size). The tube was evacuated and backfilled with
nitrogen (3 cycles). Water (0.5 mL, previously bubbled with N2
gas for 10 min) and ArI (1.5 mmol, if liquid) were added to the
reaction mixture. The tube was sealed and magnetically stirred
in a pre-heated oil bath for 24 h (note: reaction time for each sub-

5870
H. W. Lee et al. / Tetrahedron Letters 50 (2009) 5868–5871
Table 2
Table 3
Fe-catalyzed N-arylation of pyrazole under aqueous mediuma
Fe-catalyzed N-heteroarylation of pyrazolea
10 mol% FeCl3
•
6H2O
10 mol% FeCl3•
6H2O
20 mol% L1
20 mol% L1
HN
N
HN
N
2a
I
N
Het-ArI
N
K3PO4
•
H2O, 135
°C
K3PO4
•H2O, 135
°C
N
N
R
R
R
Water
Water
1l-1o
3
1a-1k
2a
3
Entry
1
Aryl
Product
%Yieldb
84
Entry
1
Aryl
Product
%Yieldb
90
N
N
N
3aa
N
1l
3la
I
I
N
N
1a
I
N
N
N
N
N
1m
3ma
3ba
3ca
Me
N
2
3
4
92
87
70
2
3
89
1b
1c
Me
MeO
F
I
N
N
1n
3na
3oa
I
N
MeO
F
N
90
I
N
N
N
N
1o
I
N
3da
N
4
82
1d
I
S
S
N
N
a
Reaction conditions: heteroaryl iodide (1.5 mmol), pyrazole (1.0 mmol),
FeCl3Á6H2O (0.1 mmol), ligand L1 (0.2 mmol), water (0.5 mL), and K3PO4ÁH2O
(2.0 mmol) under N2 for 24 h.
3ea
Cl
N
5
87
1e
Cl
I
b
Isolated yields.
N
Table 4
Fe-catalyzed N-arylation of nitrogen-containing nucleophilesa
Tracec
3fa
EtOOC
N
6
1f
EtOOC
I
N
Me
Me
Me
Me
20 mol% FeCl3•6H2O
40 mol% L1
K3PO4•H2O, 135 °C
I
NR2
HNR2
3ga
H2N
Me
N
7
53
1g
H2N
Me
I
Water
N
1h
4-9
Me
Me
Me
Me
N
N
1h
8
I
N
3ha
75
N
N
N
Me
Me
Me
Me
4: 38% yieldb
5: 87% yieldc
6: 17% yieldb
1i
3ia
I
N
9
92
N
N
N
Me
MeO
MeO
HO
Me
O
Me
N
N
Me
N
Me
1j
3ja
I
N
Me
Me
10
11
85
Me
7: 50% yieldc,d
N
8: 18% yieldc
9: 37% yieldc
HO
a
Reaction conditions: aryl iodide (1.5 mmol), nitrogen heterocycle (1.0 mmol),
FeCl3Á6H2O (0.2 mmol), ligand L1 (0.4 mmol), water (0.5 mL), and K3PO4ÁH2O
1k
3ka
I
N
76
N
(2.0 mmol) under N2 for 24 h.
Me
Me
b
GC yields.
Isolated yields.
a
c
Reaction conditions: aryl iodide (1.5 mmol), pyrazole (1.0 mmol), FeCl3Á6H2O
d
(0.1 mmol), ligand L1 (0.2 mmol), water (0.5 mL), and K3PO4ÁH2O (2.0 mmol) under
A mixture of N-substituted regioisomers.
N2 for 24 h (reaction times are not optimized for each substrate).
b
Isolated yields.
c
Starting material decomposed during the course of the reaction.
10 mol% FeCl3•6H2O
N
N
N
N
N
20 mol% L1
K3PO4•H2O, 135 °C
Water
N
HN
N
N
strate was not optimized). The tube was allowed to reach room
temperature and the reaction mixtures were extracted with ethyl
acetate (3 Â 10 mL). (Tiny amount of the aliquot was taken out
for GC-FID and GC–MS analyses). The combined organic phases
N
I
40%
Scheme 1.

H. W. Lee et al. / Tetrahedron Letters 50 (2009) 5868–5871
5871
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Acknowledgments
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