N-Arylation of nitrogen heterocycles with 2,4-difluoroiodobenzene

Article abstract of DOI:10.1016/j.tet.2008.11.036

Arylation reactions of NH-heterocycles [specifically, pyrazole, 3-(trifluoromethyl)pyrazole, imidazole and pyrrole] with 2,4-difluoroiodobenzene in the absence and presence of copper catalysis are described. The combination of fluoro and iodo substituents

Full text of DOI:10.1016/j.tet.2008.11.036

Tetrahedron 65 (2009) 855–861
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
N-Arylation of nitrogen heterocycles with 2,4-difluoroiodobenzene
*
Rukkiat Jitchati, Andrei S. Batsanov, Martin R. Bryce
Department of Chemistry, Durham University, South Road, Durham DH1 3LE, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 26 August 2008
Received in revised form 27 October 2008
Accepted 13 November 2008
Available online 18 November 2008
Arylation reactions of NH-heterocycles [specifically, pyrazole, 3-(trifluoromethyl)pyrazole, imidazole and
pyrrole] with 2,4-difluoroiodobenzene in the absence and presence of copper catalysis are described. The
combination of fluoro and iodo substituents in the same aryl substrate has facilitated both SNAr reactions
at the C–F bonds and copper-catalysed Ullmann-type coupling reactions at the C–I bond. Products arising
from regioselective reactions and multiple substitutions have been isolated, providing a range of new
N-arylated pyrazole, imidazole and pyrrole derivatives.
Keywords:
Arylation
Ó 2008 Elsevier Ltd. All rights reserved.
Nucleophilic aromatic substitution
Pyrazole
Imidazole
Pyrrole
Copper catalysis
1. Introduction
(halogen¼F or Cl) electron-withdrawing substituents and/or quite
forcing reaction conditions.5 The copper-promoted Ullmann re-
Arylated nitrogen heterocycles are common motifs in biological
and pharmaceutical science.1 For example, a range of arylpyrazole2
and arylimidazole derivatives3 have promising medicinal proper-
ties; specifically, compounds 1 and 2 have been studied recently for
their gene-activating properties on estrogen receptor alpha positive
MCF-7 breast cancer cells.2a Arylazoles are also valuable building
blocks in materials science due to their fluorescence properties, for
example, pyrazole derivative 3 (which was a target that inspired
the present study) is a ligand for blue-emitting iridium complexes.4
There is, therefore, broad interest in developing methods for the
synthesis and modification of such compounds.
action is most efficient for aryl iodides. The scope of this reaction has
recently been enhanced by the addition of ligands, such as
diamines,6 pipecolinic acid,7 sterically-hindered phosphines,8
a
mixture of 1,10-phenanthroline and dibenzylideneacetone,9
4,7-dimethoxy-1,10-phenanthroline,10 (S)-pyrrolidinylmethylimid-
azole,11 N-hydroxyimides,12 ninhydrin,13 benzotriazole,14
-glu-
D
cosamine,15 hippuric acid16 and (ꢀ)-sparteine.17 Arylbromides and
electron-deficient arylchlorides can also be substrates under these
conditions,16 although high selectivity in favour of displacement of
iodide is generally observed, e.g., for 4-bromo-iodobenzene.6d You
et al. have shown that imidazoles can be N-arylated with aryl halides
in the presence of base and a catalytic amount of CuI: the imidazole
substrate may also function as a ligand in this process.18 The CuOAc-
mediated N-arylation of indoles and carbazole with aryl iodides
under base-free and ligandless conditions has been developed.19
These metal-catalysed processes have recently been extended to
N-heteroarylations to obtain bi(heteroaryl) systems.20
F
Et
N
Ar
Ar
Et
Ar
F
N
Ar
Ar
N
N
N
N
Ar
3
1
2
Ar = 4-OH-C6H4-
Herein, we explore the reactions of NH-heterocycles (viz. pyr-
azoles, imidazole and pyrrole) with 2,4-difluoroiodobenzene 4 in
the absence and presence of copper catalysis. The rationale was that
the C–I bond should readily participate in Ullmann-type coupling
reactions, whereas the C–F bonds would activate the system to SNAr
reactions. Using 2,4-difluoroiodobenzene 4 as a substrate also en-
abled the regioselectivity of the SNAr processes to be explored.21 It
was also of interest to see if a second SNAr reaction would occur on
the initial SNAr products, which would be deactivated by the
electron-donating N-heteroaryl substituent. To our knowledge,
Aryl substrates which possess both fluoro and iodo substituents
offer unique scope for both SNAr reactions at the C–F bond(s) and
Ullmann-type coupling reactions at the C–I bond(s)da scenario that
has not been widely explored. SNAr reactions where the nucleophile
is an N-heteroatom generally require activated aryl halides
* Corresponding author. Tel.: þ44 191 3342018.
E-mail address: m.r.bryce@durham.ac.uk (M.R. Bryce).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.11.036

856
R. Jitchati et al. / Tetrahedron 65 (2009) 855–861
reactions of 2,4-difluoroiodobenzene 4 have not been studied
previously in this context.
productdwith additional confirmation from the X-ray crystal
structure of 21 (see below).22 The fluorine ortho to the iodine
substituent was observed in the range dF ꢀ90 to ꢀ98 ppm (com-
pounds 6, 9, 11 and 13); para to the iodine at dF ca. ꢀ112 ppm
(compounds 5, 8, 10 and 12). For analysis of the 1H NMR spectra
see Supplementary data.
2. Results and discussion
We initially studied the SNAr reactions of 4 with pyrazole, 3-(tri-
fluoromethyl)pyrazole, imidazole and pyrrole under basic conditions
using 1.5 equiv of the heterocycle. The results are shown in Table 1.
Under these conditions all the reactions (entries 1–4, condi-
tions b) yielded mixtures of products, which were generally
straightforward to separate by column chromatography. In all
cases the SNAr reaction occurred preferentially at C-2 rather than
C-4 (based on both 1H NMR analysis of the crude mixtures and the
relative yields of purified isomers). It is interesting to note that the
di(pyrazolyl) product 7 was also isolated in 22% yield (entry 1)
whereas analogous disubstituted products were not observed
with the less nucleophilic reagents (entries 2–4). The electron-
withdrawing effect of the trifluoromethyl group reducing the
nucleophilicity of the pyrazole nitrogen accounts for the lack of
disubstituted product in entry 2. Using 3.0 equiv of pyrazole in-
creased the yield of 7 to 56%. Using 1.0 equiv of pyrazole raised the
yield of 5 to 50%. 19F NMR spectra were especially useful
in assigning the regiochemistry of the mono-substituted
To study the copper-catalysed N-arylation, we adopted the condi-
tions reported by Taillefer et al., viz. Cu2O (5 mol %) 20% salicylald-
oxime (20 mol %) and Cs2CO3 (2 equiv) in acetonitrile.6c The results are
shown in Table 2. For all the systems studied, when using 1.5 equiv
of the heterocycle competing substitution at C–I and C–F sites was
observed, with C–I substitution being the major product (entries 1–4).
Moreover, disubstituted products (14 and 17) and trisubstituted
product 15 were also isolated from the pyrazole reactions (entries
1 and 2). An X-ray crystal structure (see below) confirmed un-
ambiguously the structure of product 17.22 Using 3.5 equiv of pyrazole
increased the yields of 14 and 15 to 35% and 13%, respectively.
The ratio of products did not change significantly when a mixture
of pyrazole (1.5 equiv), Cu2O and salicylaldoxime was stirred for
10 min at 20 ꢁC (to preform the catalyst) before adding reagent 4.
The general trend seen in Table 2 is consistent with the order of
reactivity observed previously in Ullmann-type reactions in the
azole series with aryl iodides, viz. pyrazole>imidazole>pyrrole.6d
Table 1
Arylation of N-heterocycles with 4 without Cu(I) catalysis
Z
X = NHet or F
F
Cs2CO3
Y = I
X
Y
+
HN-Het
F
I
CH3CN, 80 °C
Z = NHet or F
4
Entry
HN-Het
Product
Yielda (%)
Entry
HN-Het
Product
Yielda (%)
N
I
N
I
34b
N
N
50c,d
16c,e
66b
F
F
H
N
5
10
3
F
F
N
18b
N
H
N
N
N
15c,d
2c,e
4b
N
I
N
I
1
6
11
N
I
22b
N
15c,d
56c,e
N
N
7
CF3
N
N
N
45b
55b
F
I
F
I
H
N
N
H
N
2
4
12
8
CF3
F
F
F3C
N
6b
10c
N
I
N
I
9
13
a
Isolated yield of product, unless otherwise noted.
b
c
Standard conditions: compound 4 (1.0 equiv), the N-heterocycle (1.5 equiv) and Cs2CO3 (2 equiv) in CH3CN at 80 ꢁC, 12 h.
Yield based on 1H NMR analysis of the product mixture after column chromatography.
Pyrazole (1.0 equiv), 80 ꢁC, 12 h.
d
e
Pyrazole (3.0 equiv), 80 ꢁC, 24 h.

R. Jitchati et al. / Tetrahedron 65 (2009) 855–861
857
Table 2
Arylation of N-heterocycles with 4 with Cu(I) catalysis
X = NHet or F
Y = NHet or I
Z = NHet or F
N
OH
Z
F
OH
Cu2O, Cs2CO3
HN-Het
X
Y
+
F
I
CH3CN, 80 °C
4
Entry
HN-Het
Product
Yielda (%)
Entry
HN-Het
Product
Yielda (%)
N
I
F
N
N
2b
20b
I
N
0c,d
F
6
10
F
F
13b
0c,d
H
N
N
F
3b
F
N
N
I
3
N
N
N
3
11
H
N
N
1
F
N
N
N
20b
32b
N
35c,d
N
F
18
14
N
N
N
4b
N
N
13c,d
N
15
CF3
N
N
I
N
5b
20c
F
I
F
12
8
F
F
10b
5c
F
F
N
N
I
H
N
N
N
N
H
N
CF3
2
4
13
16
CF3
CF3
F
N
N
N
CF3
41b
35b
F
N
20
17
Isolated yield of product, unless otherwise noted.
Standard conditions: compound 4 (1.0 equiv), the N-heterocycle (1.5 equiv), Cs2CO3 (2.0 equiv), salicylaldoxime (20%) and CuO2 (5%) in CH3CN at 80 ꢁC, 12 h.
Yield based on 1H NMR analysis of the product mixture after column chromatography.
Pyrazole (3.5 equiv), 80 ꢁC, 24 h.
a
b
c
d
To extend the application of our methodology product 6 was
been exploited as a substrate for both SNAr reactions at the C–F
bond(s) and copper-catalysed coupling reactions at the C–I bond. In
this context NH-heterocycles (specifically, pyrazoles, imidazole and
pyrrole) have been reacted with 4 in the absence and presence of
copper catalysis to afford N-heterocycles bearing fluoroaryl and
iodoaryl substituents. The general trend in reactivity in both these
processes is pyrazole>imidazole>pyrrole. Regioselectivity in the
SNAr reactions and, in some cases, multiple substitutions have been
observed. These products offer scope for drug discovery and ma-
terial chemistry applications. The combination of a C–N coupling
and a subsequent Suzuki–Miyaura reaction has led to compound
reacted further in a Suzuki–Miyaura reaction with p-toluene-
boronic acid to obtain the linear triaryl product 21 in high yield
(Scheme 1). The X-ray crystal structure of 21 (Fig. 1) provided
additional support for the NMR assignment of the structure of
regioisomer 6 discussed earlier.22
3. Conclusion
The functionalisation of aryl halides is a key topic in modern
aromatic chemistry. In this context 2,4-difluoroiodobenzene 4 has

858
R. Jitchati et al. / Tetrahedron 65 (2009) 855–861
Pd(PPh3)4 (5 mol%)
Na2CO3 (2 M)
N
N
Me
(HO)2B
Me
6
+
1,4-dioxane, 100 °C
F
21 83%
Scheme 1. Suzuki-Miyaura reaction of 6.
Figure 1. X-ray molecular structures of compounds 17 at room temperature (left) and 21 at 120 K (right). Thermal ellipsoids are drawn at the 30% (17) and 50% (21) probability
levels; rotational disorder of CF3 groups is not shown.
21, which illustrates that such protocols can provide a diversity of
functionalised aryl/heteroaryl products. There is considerable
scope for extension to other mixed-halogen substrates and opti-
misation of the selectivity of the reactions by using different
nucleophiles, metal catalysts23 and ligands.
d
106 (d, JCF¼27.8 Hz), 108.5, 115.9 (d, JCF¼2.9 Hz), 126.7, 139.7, 139.8
(d, JCF¼2.9 Hz), 141.6, 141.7 (d, JCF¼9.0 Hz), 162.2 (d, JCF¼246 Hz); 19
F
NMR (CDCl3, 376 MHz):
d
ꢀ91.7; IR (neat) 3114, 2522, 2359, 1599,
1517, 1389, 1028, 752 cmꢀ1; MS (ESþ) m/z (%): 288 (Mþ, 100); HRMS
calcd for C9H6FIN2 (MHþ): 288.96326, found: 288.96327. Anal.
Calcd for C9H6FIN2: C, 37.53; H, 2.10; N, 9.72. Found: C, 37.40; H,
2.09; N, 9.67%.
4. Experimental
4.1. General
4.2.1.2. 1-(5-Fluoro-2-iodophenyl)-1H-pyrazole 5. Yield 0.81 g, 34%;
a colourless liquid; 1H NMR (CDCl3, 400 MHz):
d
6.40 (dd, J¼1.8,
2,4-Difluoroiodobenzene, pyrazole, 3-(trifluoromethyl)pyrazole,
imidazole, pyrrole salicylaldoxime and Cs2CO3 (anhydrous, 99%) were
purchased from Alfa Aesar and used without further purification.
Acetonitrile was purified using a PureSolv solvent purification system.
Copper(I) oxide and tetrakis(triphenylphosphine)palladium(0) were
purchased from Aldrich. Most 1H and 19F NMR spectra were recorded
either on a Varian Unity-400 spectrometer operating at 399.96 MHz
for 1H and 376.33 MHz for 19F or on a Bruker Avance 400 spectrometer
operating at 400.13 MHz for 1H and 100.61 MHz for 13C, respectively.
Chemical shifts are quoted downfield from TMS. MS data were
obtained using a Thermo Finnigan LTQFT instrument for ES low and
high resolution mass, and a Micromass AutoSpec spectrometer oper-
ating at 70 eV for electron impact (EI). Elemental analyses were
obtained on an Exeter Analytical Inc. CE-440 elemental analyzer.
Melting points were measured in open-end capillaries using a Stuart
Scientific SMP3 melting point apparatus. The temperatures at the
melting points were ramped at 2.5 ꢁC/min and were uncorrected.
2.4 Hz, 1H), 6.85 (ddd, J¼3.0, 8.8 Hz, JHF¼11.6 Hz, 1H), 7.13 (dd,
J¼3.0 Hz, JHF¼9.2 Hz, 1H), 7.68 (d, J¼1.8 Hz, 1H), 7.71 (d, J¼2.4 Hz,
1H), 7.81 (dd, JHF¼5.8 Hz, J¼8.8 Hz, 1H); 13C NMR (CDCl3, 100 MHz):
d
86.5 (d, JCF¼4.4 Hz), 106.7, 115.5 (d, JCF¼23.4 Hz), 117.1 (d,
JCF¼20.5 Hz), 130.8, 140.8 (d, JCF¼8.8 Hz), 140.9, 144.2 (d,
JCF¼10.2 Hz), 162.5 (d, JCF¼250 Hz); 19F NMR (CDCl3, 376 MHz):
d
ꢀ112.1; IR (neat) 3726, 3102, 3102, 2360, 1583, 1468, 1191, 861,
749 cmꢀ1; MS (ESþ) m/z (%): 289.1 (MHþ, 100); HRMS calcd for
C9H6FIN2 (MHþ): 288.96326, found: 288.96333.
4.2.1.3. 2,4-Di(1-1H-pyrazolyl)-iodobenzene 7. Yield 0.61 g, 22%;
white solid; mp 96.0–98.0 ꢁC; 1H NMR (CDCl3, 400 MHz):
d 6.44
(dd, J¼1.5, 2.5 Hz, 1H), 6.46 (dd, J¼1.5, 2.5 Hz, 1H), 7.52 (dd, J¼2.5,
8.5 Hz, 1H), 7.69 (d, J¼1.5 Hz, 1H), 7.74 (d, J¼1.5 Hz, 1H), 7.75 (d,
J¼2.5 Hz, 1H), 7.77 (d, J¼2.5 Hz, 1H), 7.91 (d, J¼2.5 Hz, 1H), 7.96 (d,
J¼8.5 Hz, 1H); 13C NMR (CDCl3, 100 MHz):
d 89.4, 106.8, 108.4, 118.2,
120.2, 120.0, 126.6, 131.0, 140.7, 140.8, 141.0, 141.7, 144.0; IR (neat)
3735, 2360, 1524, 1267, 963, 847, 749 cmꢀ1; MS (ESþ) m/z (%): 337.0
(MHþ, 100); HRMS calcd for C12H9IN4 (MHþ) 336.99448, found:
336.99447.
4.2. Reactions without Cu(I) catalysis
4.2.1. Compounds 5, 6, 7
The analogous reaction using pyrazole (1.0 equiv) gave 5 (50%), 6
(15%) and 7 (15%).
The analogous reaction using pyrazole (3.0 equiv) at 80 ꢁC for
24 h gave 5 (16%), 6 (2%) and 7 (56%).
The reaction of pyrazole (0.85 g, 12.5 mmol), 2,4-difluoro-
iodobenzene 4 (1.0 mL, 8.3 mmol) and Cs2CO3 (5.4 g, 16.7 mmol) in
acetonitrile (10 mL)andcolumnchromatography (SiO2, eluentether/
DCM, 0:1 to 1:5 v/v) gave the following products in order of elution.
4.2.2. Compounds 8, 9
4.2.1.1. 1-(3-Fluoro-4-iodophenyl)-1H-pyrazole 6. Yield 0.43 g, 18%;
The reaction of 3-(trifluoromethyl)pyrazole (1.7 g, 12.5 mmol),
2,4-difluoroiodobenzene 4 (1.0 mL, 8.3 mmol) and Cs2CO3 (5.4 g,
16.7 mmol) in acetonitrile (10 mL) and column chromatography
(SiO2, eluent DCM/hexane, 1:1 v/v) gave the following products in
order of elution.
a white solid; mp 76.0–77.5 ꢁC; 1H NMR (CDCl3, 400 MHz):
d 6.39
(dd, J¼1.5, 2.5 Hz,1H), 7.17 (dd, J¼2.5, 8.5 Hz,1H), 7.48 (dd, J¼2.5 Hz,
JHF¼9.0 Hz, 1H), 7.71 (d, J¼1.5 Hz, 1H), 7.76 (dd, JHF¼7.0 Hz,
J¼8.5 Hz, 1H), 7.88 (d, J¼2.5 Hz, 1H); 13C NMR (CDCl3, 100 MHz):

R. Jitchati et al. / Tetrahedron 65 (2009) 855–861
859
4.2.2.1. 1-(5-Fluoro-2-iodophenyl)-3-trifluoromethyl-1H-pyrazole
JHF¼11.6 Hz, 1H), 7.06 (d, J¼3.0 Hz, JHF¼9.0 Hz, 1H), 7.88 (dd,
8. Yield 1.33 g, 45%; a colourless liquid; 1H NMR (CDCl3, 400 MHz):
JHF¼5.5 Hz, J¼8.5 Hz, 1H); 13C NMR (CDCl3, 125 MHz):
d 88.6 (d,
d
6.74 (dd, JHF¼0.6 Hz, J¼2.4 Hz, 1H), 6.99 (ddd, J¼3.0, 8.8 Hz,
JCF¼3.8 Hz), 109.7 (2C), 115.8 (d, JCF¼23.0 Hz), 116.9 (d, JCF¼21.0 Hz),
122.1 (2C), 140.9 (d, JCF¼8.6 Hz), 145.2 (d, JCF¼10.5 Hz), 162.9 (d,
JHF¼11.9 Hz, 1H), 7.40 (dd, J¼3.0 Hz, JHF¼8.5 Hz, 1H), 7.80 (qd,
JHF¼0.9 Hz, J¼2.4 Hz, 1H), 7.92 (dd, J¼8.8 Hz, JHF¼5.8 Hz, 1H); 13C
JCF¼250 Hz); 19F NMR (CDCl3, 376 MHz):
d
ꢀ112.7; IR (neat) 3140,
NMR (CDCl3, 125 MHz):
d
86.9 (d, JCF¼3.8 Hz), 105.5 (q, JCF¼1.9 Hz),
2798, 1530, 1480, 1125, 768 cmꢀ1; MS (ESþ) m/z (%): 287.1 (MHþ,
100); HRMS calcd for C10H7FIN (MHþ): 287.96801, found:
287.96825.
116.3 (d, JCF¼24.9 Hz), 118.7 (d, JCF¼22.0 Hz), 121.1 (q, JCF¼270 Hz),
132.8, 141.3 (d, JCF¼7.7 Hz), 143.6 (d, JCF¼9.6 Hz), 144.7 (q,
JCF¼38.4 Hz), 162.9 (d, JCF¼252 Hz); 19F NMR (CDCl3, 376 MHz):
d
ꢀ111.6, ꢀ62.5; IR (neat) 3732, 2359, 1532, 1258, 968, 843,
4.2.4.2. 1-(3-Fluoro-4-iodophenyl)-1H-pyrrole 13. Yield 0.24 g, 10%;
747 cmꢀ1; MS (EI) m/z (%): 356 (Mþ, 100), 337 (MþꢀF, 10), 229
(MþꢀI, 100); MS (ESþ) m/z (%): 356.8 (MHþ, 100); HRMS calcd for
C10H6F4I2N2 (MHþ): 356.95064, found: 356.95060.
a colourless liquid; 1H NMR (CDCl3, 400 MHz):
d
6.39 (t, J¼2.1 Hz,
2H), 7.00 (t, J12¼2.4 Hz, J13¼8.5 Hz, 1H), 7.07 (t, J¼2.1 Hz, 2H), 7.14
2
3
(d, J12¼2.4 Hz, JHF¼9.1 Hz, 1H), 7.77 (dd, JHF¼7.0 Hz, J13¼8.5 Hz,
1H); 19F NMR (CDCl3, 376 MHz):
d
ꢀ91.8; IR (neat) 3148, 2787, 1532,
4.2.2.2. 1-(3-Fluoro-4-iodophenyl)-4-trifluoromethyl-1H-pyrazole
1485, 1120, 765 cmꢀ1; MS (EI) m/z (%): 287 (Mþ, 100), 160 (MþꢀI,
100). 1H NMR showed that 13 was not completely separated from
traces of 12.
9. Yield 0.18 g, 6%; a colourless liquid; 1H NMR (CDCl3, 400 MHz):
d
6.77 (dd, JHF¼0.5 Hz, J¼2.4 Hz, 1H), 7.61 (dd, JHF¼2.6 Hz, J¼8.6 Hz,
1H), 7.85 (dd, J¼0.5 Hz, JHF¼8.8 Hz, 1H), 8.00–8.01 (m, 1H), 8.07 (dd,
J¼0.5, 8.6 Hz, 1H); 19F NMR (CDCl3, 376 MHz):
d
ꢀ97.8, ꢀ62.8; IR
(neat) 3730, 2360, 1518, 1267, 845, 751 cmꢀ1; MS (EI) m/z (%): 356
(Mþ, 100), 337 (MþꢀF, 10), 229 (MþꢀI, 100); MS (ESþ) m/z (%):
356.8 (MHþ, 100); HRMS calcd for C10H6F4I2N2 (MHþ): 356.95064,
found: 356.95063. 1H NMR showed that 9 was not completely
separated from traces of 8.
4.3. Reactions with Cu(I) catalysis
4.3.1. Compounds 3, 6, 14, 15
The reaction of pyrazole (0.85 g, 12.5 mmol), 2,4-difluoro-
iodobenzene
4
(1.0 mL, 8.3 mmol), salicylaldoxime (0.23 g,
1.67 mmol), Cs2CO3 (5.4 g, 16.7 mmol) and Cu2O (60 mg,
0.42 mmol) and column chromatography (SiO2, eluent ether/DCM,
0:1 to 1:5 v/v) gave the following compounds in order of elution.
Compound 6 (39 mg, 2%) was eluted first, which was spectro-
scopically identical with the sample above.
4.2.3. Compounds 10, 11
The reaction of imidazole (0.85 g, 12.5 mmol), 2,4-difluoro-
iodobenzene 4 (1.0 mL, 8.3 mmol) and Cs2CO3 (5.4 g, 16.7 mmol)
and column chromatography (SiO2, eluent haxane/DCM, 4:1 to 1:1
v/v) gave the following products in order of elution.
4.3.1.1. 1-(2,4-Difluorophenyl)-1H-pyrazole 3. Yield 0.25 g, 13%;
4.2.3.1. 1-(5-Fluoro-2-iodophenyl)-1H-imidazole 10. Yield 1.8 g,
a colourless liquid; 1H NMR (CDCl3, 400 MHz):
d
6.45 (t, J¼1.5 Hz,
66%; a white solid; mp 67.0–68.5 ꢁC; 1H NMR (CDCl3, 400 MHz):
1H), 6.93–6.99 (m, 2H), 7.71 (d, J¼1.5 Hz, 1H), 7.83 (td, JHF¼6.0 Hz,
d
6.97 (ddd, J¼3.0, 8.5 Hz, JHF¼11.6 Hz, 1H), 7.07 (d, J¼1.0 Hz, 1H),
J¼8.0 Hz, 1H), 7.90 (t, JHF¼2.4 Hz 1H); 13C NMR (CDCl3, 100 MHz):
7.08 (dd, J¼3.0 Hz, JHF¼8.5 Hz, 1H), 7.21 (d, J¼1.0 Hz, 1H), 7.64 (s,
d
105.0 (dd, JCF¼24.9, 26.3 Hz), 107.5, 112.1 (dd, JCF¼21.9, 4.4 Hz),
1H), 7.91 (dd, JHF¼5.0 Hz, J¼8.5 Hz, 1H); 13C NMR (CDCl3, 100 MHz):
125.2 (dd, JCF¼8.8, 2.9 Hz), 125.6 (dd, JCF¼7.3, 10.2 Hz), 130.6 (d,
JCF¼8.7 Hz), 140.9, 151.7 (dd, JCF1¼251.8 Hz, JCF¼11.7 Hz), 161.3 (dd,
d
88.8 (d, JCF¼2.9 Hz), 115.8 (d, JCF¼23.4 Hz), 118.1 (d, JCF¼21.9 Hz),
120.4, 129.9, 137.4, 141.1 (d, JCF¼8.8 Hz), 141.5 (d, JCF¼10.2 Hz), 162.9
JCF¼250.3, 11.7 Hz); 19F NMR (CDCl3, 376 MHz):
ꢀ121.2, ꢀ112.0; IR
d
(d, JCF¼252 Hz); 19F NMR (CDCl3, 376 MHz):
d
ꢀ111.7; IR (neat)
(neat) 3730, 3109, 2360, 1583, 1474, 1390, 1193, 863, 748 cmꢀ1; MS
(EI) m/z (%): 180 (Mþ, 100); MS (ESþ) m/z (%): 181.1 (MHþ, 100);
HRMS calcd for C9H7F2N2 (MHþ): 181.05718, found: 181.05715.
3733, 2360, 1496, 1243, 1189, 1051, 846, 748 cmꢀ1; MS (ESþ) m/z
(%): 289.0 (MHþ, 100); HRMS calcd for C9H6FIN2 (MHþ, 100):
288.96326, found: 288.96320.
4.3.1.2. 3,4-Di(1H-pyrazolyl)fluorobenzene 14. Yield 0.36 g, 20%;
4.2.3.2. 1-(3-Fluoro-4-iodophenyl)-1H-imidazole 11. Yield 80 mg,
a colourless liquid; 1H NMR (CDCl3, 400 MHz):
d 6.25 (s, 1H), 6.31 (s,
4%; a white solid; mp 106.5–108.0 ꢁC; 1H NMR (CDCl3, 400 MHz):
1H), 6.82 (s, 1H), 7.08 (s, 1H), 7.15 (td, J¼8.8, 2.3 Hz, 1H), 7.50 (dd,
2
d
6.98 (dd, J¼2.5 Hz, JHF¼9.0 Hz, 1H), 7.11 (dd, J¼2.5, 8.5 Hz, 1H),
J¼2.3 Hz, JHF¼8.8 Hz, 1H), 7.58 (dd, JHF¼5.5 Hz, J¼8.8 Hz, 1H), 7.67
7.19 (s, 1H), 7.24 (s, 1H), 7.81 (dd, JHF¼7.0 Hz, J¼8.5 Hz, 1H), 7.84 (s,
(s, 1H), 7.70 (s, 1H); 13C NMR (100 MHz, CDCl3):
d 162.0 (d,
1H); 13C NMR (CDCl3, 100 MHz):
d
78.9 (d, JCF¼24.9 Hz), 109.0 (d,
JCF¼250 Hz), 141.5, 141.3, 136.5 (d, JCF¼11.0 Hz), 130.9, 130.2, 129.9
JCF¼26.3 Hz), 117.8, 118.2 (d, JCF¼4.4 Hz), 131.0, 135.2, 138.8 (d,
(d, JCF¼3.7 Hz), 129.2 (d, JCF¼9.5 Hz), 115.4 (d, JCF¼17.7 Hz), 113.5 (d,
JCF¼8.8 Hz), 140.4, 162.2 (d, JCF¼247 Hz); 19F NMR (CDCl3,
JCF¼26.0 Hz), 108.0, 107.7; 19F NMR (CDCl3, 376 MHz):
d
ꢀ110.5; IR
376 MHz):
d
ꢀ90.5; IR (neat) 2518, 2359, 1571, 1179, 852, 753 cmꢀ1
;
(neat) 3725, 3111, 2360, 1580, 1465, 1382, 1158, 870, 745 cmꢀ1; MS
(ESþ) m/z (%): 229.2 (MHþ, 100); HRMS calcd for C12H10N4F (MHþ):
229.08840, found: 229.08848.
MS (EI) m/z (%): 287.9 (Mþ, 100), 260.8 (MþꢀI, 30); MS (ESþ) m/z
(%): 289.0 (MHþ, 100); HRMS calcd for C9H6FIN2 (MHþ): 288.96326,
found: 288.96322.
4.3.1.3. 1,2,4-Tris(1H-pyrazolyl)benzene 15. Yield 80 mg, 4%; a col-
4.2.4. Compounds 12, 13
ourless liquid; 1H NMR (CDCl3, 400 MHz):
d
6.26 (t, J¼2.5 Hz, 1H),
The reaction of pyrrole (0.85 mL, 12.5 mmol), 2,4-difluoro-
iodobenzene 4 (1.0 mL, 8.3 mmol) and Cs2CO3 (5.4 g, 16.7 mmol)
and column chromatography (SiO2, eluent hexane) gave a mixture
of 12 and 13 (1.55 g, 65%, ca. 5:1 ratio by 1H NMR analysis of the
crude mixture). Crystallisation of the mixture from hexane gave the
following compounds.
6.28 (t, J¼2.0 Hz, 1H), 6.45 (t, J¼2.5 Hz, 1H), 6.95 (d, J¼2.5 Hz, 1H),
7.01 (d, J¼2.0 Hz, 1H), 7.67–7.71 (m, 4H), 7.83 (dd, J¼2.5, 8.5 Hz, 1H),
7.98 (d, J¼2.5 Hz, 1H), 8.02 (d, J¼2.5 Hz, 1H); 13C NMR (CDCl3,
100 MHz):
d 107.7, 107.8, 108.4, 116.6, 118.5, 126.9, 128.2, 130.4,
130.6, 131.8, 135.4, 140.0, 141.3, 141.4, 141.8; IR (neat) 3727, 2360,
1586, 1479, 1275, 1129, 865, 764 cmꢀ1; MS (ESþ) m/z (%): 277.2
(MHþ, 32), 299.2 (MþþNaþ, 100); HRMS calcd for C15H12N6
(MþþNaþ): 299.10157, found: 299.10169.
4.2.4.1. 1-(5-Fluoro-2-iodophenyl)-1H-pyrrole 12. Yield 1.31 g, 55%;
a white solid; mp 70–71.5 ꢁC; 1H NMR (CDCl3, 400 MHz):
d
6.34 (t,
The analogous reaction using pyrazole (3.5 equiv) at 80 ꢁC for
24 h gave 14 (35%) and 15 (13%).
J¼2.0 Hz, 2H), 6.82 (t, J¼2.0 Hz, 2H), 6.89 (ddd, J¼3.0, 8.5 Hz,

860
R. Jitchati et al. / Tetrahedron 65 (2009) 855–861
4.3.2. Compounds 8, 16, 17
0.42 mmol) and column chromatography (SiO2, eluent hexane)
gave the following compounds in order of elution.
The reaction of 3-(trifluoromethyl)pyrazole (1.7 g, 12.5 mmol),
2,4-difluoroiodobenzene 4 (1.0 mL, 8.3 mmol), salicylaldoxime
(0.23 g, 1.67 mmol), Cs2CO3 (5.4 g, 16.7 mmol) and Cu2O (60 mg,
0.42 mmol) and column chromatography (SiO2, eluent DCM/
hexane, 1:1 v/v) gave the following compounds in order of
elution.
Compound 8 (0.15 g, 5%) was eluted first, which was spectro-
scopically identical with the sample above, followed by compounds
17 and 16.
Compounds 12 and 13 (57 mg, 25%, 4:1 ratio by 1H NMR), which
were not separated, followed by compound 20.
4.3.4.1. 1-(2,4-Difluorophenyl)-1H-pyrrole 20. Yield 0.60 g, 35%;
a colourless liquid; 1H NMR (CDCl3, 400 MHz):
d
6.43 (t, J¼2.0 Hz,
2H), 6.96–7.05 (m, 3H), 7.07–7.15 (m, 1H), 7.40 (td, JHF¼5.7 Hz,
J¼8.8 Hz, 1H); 13C NMR (CDCl3, 125 MHz):
d
105.6 (dd, JCF¼24.2,
26.3 Hz), 109.7, 112.7 (dd, JCF¼3.9, 21.5 Hz), 121.5, 123.2 (dd, JCF¼2.0,
8.9 Hz), 124.9 (d, JCF¼10.5 Hz), 156.5 (dd, JCF¼11.5, 250 Hz), 161.0
4.3.2.1. 3,4-Bis(4-trifluoromethyl-1H-pyrazolyl)fluorobenzene 17. Yield
(dd, JCF¼10.1, 251 Hz); 19F NMR (CDCl3, 376 MHz):
ꢀ112.7, ꢀ120.6;
d
1.24 g, 41%; a white solid; mp 83.4–84.0 ꢁC; 1H NMR (CDCl3,
IR (neat) 3138, 2854, 2755, 1540, 1482, 1124, 1075, 748 cmꢀ1; MS
(ESþ) m/z (%): 287.1 (MHþ, 100); HRMS calcd for C10H7F2N (MHþ):
180.06248, found: 180.06240.
400 MHz):
d
6.58 (d, J¼2.5 Hz, 1H), 6.61 (d, J¼2.0 Hz, 1H), 7.14 (d,
J¼2.0 Hz, 1H), 7.27 (d, J¼2.5 Hz, 1H), 7.31 (ddd, J¼2.5, 8.5 Hz,
JHF¼11.6 Hz, 1H), 7.50 (dd, J¼2.5 Hz, JHF¼8.5 Hz, 1H), 7.67 (dd, JHF
¼
5.0 Hz, J¼8.5 Hz, 1H); 13C NMR (CDCl3, 125 MHz):
d 106.3 (d,
4.4. 1-(2-Fluoro-40-methylbiphenyl-4-yl)-1H-pyrazole 21
JCF¼1.9 Hz),114.5 (d, JCF¼25.9 Hz),117.1 (d, JCF¼22.1 Hz),119.8 (q, JCF
¼
277 Hz), 121.9 (q, JCF¼277 Hz), 129.5 (d, JCF¼9.6 Hz), 130.1 (d,
JCF¼3.9 Hz), 132.1, 132.8, 136.1 (d, JCF¼10.5 Hz), 144.7–145.2 (m, 2C),
A mixture of Pd(PPh3)4 (40 mg, 0.03 mmol), compound 6 (0.20 g,
0.69 mmol), Na2CO3 (2 M, 2.0 mL) and p-tolueneboronic acid
(0.11 g, 0.83 mmol) in degassed 1,4-dioxane (20 mL) was stirred and
heated in an oil bath at 100 ꢁC overnight. The reaction mixture was
cooled to room temperature, diluted with dichloromethane and
water. The resulting organic layer was washed with water and
saturated NaCl solution, separated and dried over MgSO4. The sol-
vent was removed in vacuo to yield the crude product, which was
purified by column chromatography (SiO2, eluent ether/DCM, 1:5 v/
v) to give 21 (0.14 g, 83%); a white solid; mp 115.5–117 ꢁC; 1H NMR
162.6 (d, JCF¼254 Hz); 19F NMR (CDCl3, 376 MHz):
d
ꢀ107.9, ꢀ62.8,
ꢀ62.7; IR (neat) 3730, 3115, 2360,1512,1272,1130, 755 cmꢀ1; MS (EI)
m/z (%): 364.0 (Mþ, 100); 295.0 (MþꢀCF3, 70); MS (ESþ) m/z (%):
365.1 (MHþ, 100); HRMS calcd for C14H7F7N4 (MþþNaþ): 387.04512,
found: 387.04505.
4.3.2.2. 1-(2,4-Difluorophenyl)-3-trifluoromethyl-1H-pyrazole 16.
Yield 0.2 g, 10%; a white solid; mp 29–30 ꢁC; 1H NMR (CDCl3,
200 MHz):
d
6.73 (d, J¼1.9 Hz, 1H), 6.97–7.01 (m, 2H), 7.85 (td,
(CDCl3, 400 MHz):
d
2.41 (s, 3H), 6.50 (t, J¼2.4 Hz, 1H), 7.27
JHF¼5.8 Hz, J¼8.1 Hz, 1H), 7.95 (d, J¼1.9 Hz, 1H); 13C NMR (CDCl3,
(d, J¼7.6 Hz, 2H), 7.46 (d, J¼2.0 Hz, 1H), 7.48 (d, J¼2.0
Hz, 1H), 7.52–7.60 (m, 3H), 7.44 (d, J¼2.4 Hz, 1H), 7.94 (d, J¼2.4 Hz,
2
100 MHz):
d
105.4 (t, JCF¼26.9 Hz), 106.0, 112.6 (dd, JCF1¼22.2 Hz,
1H); 13C NMR (CDCl3, 125 MHz):
d
107.4 (d, JCF¼28.8 Hz), 108.2,
JCF2¼3.2 Hz), 121.4 (q, JCF¼269.5 Hz), 124.5–124.6 (m), 126.4 (d,
JCF¼9.5 Hz), 132.4 (d, JCF¼9.5 Hz), 144.4 (d, JCF¼38.0 Hz), 154.4 (dd,
114.6 (d, JCF¼3.8 Hz),126.8,127.0 (d, JCF¼13.4 Hz),128.8,128.9,129.4
JCF1¼252.0 Hz,
JCF2¼12.7 Hz),
161.5
(dd,
JCF1¼252.0 Hz,
(2C), 131.5 (d, JCF¼4.8 Hz), 132.2, 137.9, 140.3 (d, JCF¼10.5 Hz), 160.5
3JCF2¼11.0 Hz); 19F NMR (CDCl3, 376 MHz):
ꢀ120.9, ꢀ109.6, ꢀ62.7;
d
(d, JCF¼248 Hz); 19F NMR (CDCl3, 376 MHz):
d
ꢀ115.8; IR (neat)
IR (neat) 3731, 3110, 2360, 1512, 1275, 1120, 861, 752 cmꢀ1; MS (EI)
m/z (%): 248 (Mþ,100); 229 (MþꢀF,10),179 (MþꢀCF3, 10); MS (ESþ)
m/z (%): 349.0 (MHþ, 100); HRMS calcd for C10H6F5N2 (MHþ):
249.04511, found: 249.04515.
3728, 2928, 2524, 2359, 1500, 1390, 1267, 1037, 850, 751 cmꢀ1; MS
(ESþ) m/z (%): 253.1 (MHþ, 100); HRMS calcd for C16H14FN2 (MHþ):
253.11355, found: 253.11351.
Acknowledgements
4.3.3. Compounds 10, 11, 18
The reaction of imidazole (0.85 g, 12.5 mmol), 2,4-difluoro-
The authors thank the Royal Thai Government for a scholarship
to R.J.
iodobenzene
4
(1.0 mL, 8.3 mmol), salicylaldoxime (0.23 g,
1.67 mmol), Cs2CO3 (5.4 g, 16.7 mmol) and Cu2O (60 mg,
0.42 mmol) and column chromatography (SiO2, eluent ether/DCM,
0:1 to 1:1 v/v) gave the following compounds in order of elution.
Compounds 10 (0.48 g, 20%) and 11 (70 mg, 3%) were eluted
first, which were spectroscopically identical with the samples
above, followed by compound 18.
Supplementary data
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2008.11.036.
4.3.3.1. 1-(2,4-Difluorophenyl)-1H-imidazole 18. Yield 0.48 g, 32%;
References and notes
a white solid; mp 60.0–62.0 ꢁC; 1H NMR (CDCl3, 400 MHz):
d
6.97–
7.06 (m, 2H), 6.20 (s, 1H), 6.22 (s, 1H), 7.37 (td, JHF¼6.1 Hz, J¼8.8 Hz
1H), 7.75 (s, 1H); 13C NMR (CDCl3, 175 MHz):
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Elsevier: Oxford, 1996; (b) Craig, P. N. In Comprehensive Medicinal Chemistry;
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d
105.4 (dd, JCF¼23.8,
26.5 Hz), 112.1 (dd, JCF¼3.9, 22.5 Hz), 119.6 (d, JC¼1.6 Hz), 121.8 (dd,
JCF¼3.9, 11.8 Hz), 126.2 (dd, JCF¼1.9, 9.9 Hz), 129.8, 136.9 (d,
JCF¼3.3 Hz), 155.3 (dd, JCF¼12.3, 254 Hz), 161.5 (dd, JCF1¼11.0,
251 Hz); 19F NMR (CDCl3, 376 MHz):
d
ꢀ119.7, ꢀ109.5; IR (neat)
3735, 3109, 2360, 1581, 1425, 1243, 1185, 1052, 823, 745 cmꢀ1; MS
(EI) m/z (%): 180 (Mþ, 100); MS (ESþ) m/z (%): 181.1 (MHþ, 100);
HRMS calcd for C9H6F2N2 (MHþ): 181.05718, found: 181.05714.
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has been described: Finar, I. L.; Rackman, D. M. J. Chem. Soc. B 1968, 211–214. No
characterisation data were given for 3.
4.3.4. Compounds 12, 13, 20
The reaction of pyrrole (0.85 mL, 12.5 mmol), 2,4-difluoro-
iodobenzene
4
(1.0 mL, 8.3 mmol), salicylaldoxime (0.23 g,
1.67 mmol), Cs2CO3 (5.4 g, 16.7 mmol) and Cu2O (60 mg,

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Chem., Int. Ed. 2006, 45, 6523–6527.
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22. Crystal data: C14H7F7N4 17, M¼364.24, monoclinic (C2/c, no. 15), a¼18.4627(15),
b¼9.8208(8), c¼18.659(2) Å,
b
¼112.86(2)ꢁ, V¼3117.5(5) Å3, Z¼8, R1[I>2
(I)]¼0.
s
049, wR2(all data)¼0.133, CCDC-698164. C16H13FN2 21, M¼252.28, ortho-
rhombic (Pbca, no. 61), a¼8.8599(7), b¼16.5827(14), c¼16.8780(15) Å, V¼2479.
7(4) Å3, Z¼8, R1[I>2
(I)]¼0.051, wR2(all data)¼0.153, CCDC-698165.
s
23. Efficient palladium and iron-catalysed N-arylations have also been reported. (a)
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D.; Strieter, E.; Buchwald, S. J. Am. Chem. Soc. 2006, 128, 3584–3591 and ref-
erences therein; (b) Iron: Correa, A.; Bolm, C. Angew. Chem., Int. Ed. 2007, 46,
8862–8865.
13. Huang, Y.-Z.; Gao, J.; Ma, H.; Miao, H.; Xu, J. Tetrahedron Lett. 2008, 49, 948–951.
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