Copper(II) fluoride-catalyzed N-arylation of heterocycles with halothiophenes

Article abstract of DOI:10.1016/j.tetlet.2010.07.094

A novel, cheap copper(II) fluoride-mediated N-arylation of heterocycles with halothiophenes is described. The yield of the pyrazolylthiophene strongly depends on the nature of the initial thiophene. The molecular structure of 3,5-dimethyl-1-(50-methyl-[2,

Full text of DOI:10.1016/j.tetlet.2010.07.094

Tetrahedron Letters 51 (2010) 5052–5055
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Copper(II) fluoride-catalyzed N-arylation of heterocycles with halothiophenes
*
Pavel Arsenyan , Edgars Paegle, Alla Petrenko, Sergey Belyakov
Latvian Institute of Organic Synthesis, Aizkraukles 21, LV-1006 Riga, Latvia
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 19 February 2010
Revised 3 July 2010
Accepted 16 July 2010
Available online 23 July 2010
A novel, cheap copper(II) fluoride-mediated N-arylation of heterocycles with halothiophenes is described.
The yield of the pyrazolylthiophene strongly depends on the nature of the initial thiophene. The molec-
ular structure of 3,5-dimethyl-1-(50-methyl-[2,20]bithienyl-5-yl)-1H-pyrazole was studied by X-ray
diffraction.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Arylation
Bithiophene
Pyrazole
Thiophene
X-ray crystal structure
N-Aryl heterocycles are widely used fragments in the field of
pharmaceutical chemistry.1a Arylation of heterocyclic nitrogen is a
difficult problem.1b The first ipso substitution of an aryl halide by a
nucleophile in the presence of copper(II) triflate, 1,10-phenanthro-
line, dibenzylideneacetone, and cesium carbonate was reported by
Buchwald and co-workers.2 Investigations in the field of copper-
catalyzed arylation of N-heterocycles have gained attention, as
reflected by the increasing number of reports in the literature.
Various copper(I) and copper(II) salts and their complexes with
N-, O-, and P-ligands were investigated as catalysts for the N-aryla-
tion of nitrogen-containing heterocycles. According to the literature,
copper(I) iodide was the most promising source of copper in this
type of reaction in the presence of potassium phosphate in toluene.3
Recently, Lakshmi Kantam and co-workers reported that copper-
exchanged fluoroapatite is an effective heterogeneous catalyst for
the N-arylation of heterocycles with bromo- and iodoarenes in
DMSO.4
(Table 1). It was foundthat the widely used DMEDA, TMEDA, and sal-
icylaldoxime were ineffective in CuF2-mediated coupling even after
heating for 96 h. However, the use of 0.25 equiv of o-phenanthroline
catalyzed the current reaction successfully and the desired product,
1-(4-methoxyphenyl)-3,5-dimethylpyrazole6a (3) was obtained in
81% yield. On performing the same reaction in DMSO, the yield of
compound 3 was slightly lower (78%); no product was obtained in
xylene. According to our experimental data, 2,2,6,6-tetramethyl-
3,5-heptanedione was a good ligand for the CuF2-mediated coupling
(73% yield, entry 5), however, it is quite expensive. Finally, we chose
1,10-phenanthroline as the ligand and DMF as the solvent for further
investigations.
Reactions of 4-iodoanisole (1) with various five-membered
N-heterocycles are presented in Scheme 1. Using our new catalytic
system, pyrazole was successfully N-arylated with 1 in almost
quantitative yield (4,6b 98%). 1-(4-Methoxyphenyl)-4-bromo-3,5-
dimethylpyrazole (5)6c and 1-(4-methoxyphenyl)imidazole (6)6b
were obtained in good yields, however, our attempt to arylate
benzimidazole was not impressive, the desired product 76b being
obtained in only 16% yield. Notably, arylated indole 86d and ethyl
5-benzyloxyindol-2-ylcarboxylate 96e were prepared in good
yields (72% and 60%, respectively).
Our experience with thiophene chemistry5 inspired us to inves-
tigate the incorporation of five-membered N-heterocycles on thio-
phene and bithiophene cores in the presence of copper(II) fluoride
with the purpose of optimizing the conditions for the coupling and
to find a cheap and convenient method.
Typically, copper-mediated coupling of aryl halides with N-het-
erocycles is performed in aprotic solvents in the presence of a base
and ligand. 4-Iodoanisole (1) and 3,5-dimethylpyrazole (2) were
chosen as model compounds. Our investigation started with the
reactions of 1 and 2 in DMF in the presence of potassium carbonate
as base with the purpose of finding the best and the cheapest ligand
Heteroarylthiophenes have attracted significant attention as
useful building blocks in biologically active compounds and as
materials showing conductive, semiconductive, non-linear, and
liquid crystalline characteristics.7 Thus, we investigated the intro-
duction of a pyrazole ring at the a-position of thiophene via the reac-
tion of 2-iodothiophene and 3,5-dimethylpyrazole. The desired
product 10 was formed in moderate yield (65%) after heating for
72 h in DMF using copper(II) fluoride as the catalyst in the presence
of 1,10-phenanthroline and potassium carbonate as the base (Table
* Corresponding author. Tel.: +371 29849464.
E-mail address: pavel.arsenyan@lycos.com (P. Arsenyan).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.07.094

P. Arsenyan et al. / Tetrahedron Letters 51 (2010) 5052–5055
5053
Table 1
CuF2-catalyzed reaction of 4-iodoanisole with 3,5-dimethylpyrazole
I
N
N
+
HN
N
O
O
1
2
3
Entry
Ligand
Catalyst equiv
Base
Solvent
Time (h)
Yield (%)
1
2
3
4
DMEDA
TMEDA
1,10-Phenanthroline
Salicyl aldoxime
0.25
0.25
0.25
0.25
K2CO3
K2CO3
K2CO3
K2CO3
DMF
DMF
DMF
DMF
96
96
96
96
18
4
81
10
O
O
5
0.25
K2CO3
DMF
96
73
6
7
8
—
—
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
K2CO3
K2CO3
K2CO3
DMF
96
72
72
72
22
22
48
48
48
6
78
36
1,10-Phenanthroline
1,10-Phenanthroline
1,10-Phenanthroline
1,10-Phenanthroline
1,10-Phenanthroline
1,10-Phenanthroline
1,10-Phenanthroline
1,10-Phenanthroline
0.25
0.25
0.25
0.25
0.25
0.2
DMSO
DMAC
xylene
DMF
DMF
DMF
9
0
10
11
12
13
14
ꢁ8
ꢁ10
20
52
50
0.4
0.6
DMF
DMF
OBn
Br
N
N
N
O
4
N
N
98%
O
5
O
O
EtO
9
I
83%
60%
O
80%
N
N
1
72%
N
16%
O
6
8
O
N
N
7
O
Scheme 1. Reagents and conditions: 4-iodoanisole (1 equiv), N-heterocycle (1.2 equiv), copper(II) fluoride (0.5 equiv), 1,10-phenanthroline (0.5 equiv), K2CO3 (3 equiv), DMF,
140 °C, 72 h.
2). It was found that 4-bromo-3,5-dimethylpyrazole reacted with 2-
iodothiophene in lower yield to afford the corresponding 4-bromo-
3,5-dimethyl-1-(thien-2-yl)-1H-pyrazole (11),6f however, a more
promising result was obtained in the reaction with imidazole
(12,6g 59%). 2,5-Di(3,5-dimethylpyrazolyl)thiophene (13)6h was
synthesized in moderate yield from 2,5-dibromothiophene (bromo
substituents are not as convenient leaving groups under the current
reaction conditions). 5-Iodo-50-methyl-2,20-bithiophene was suc-
cessfully converted into the corresponding 3,5-dimethyl-1-(50-
methyl-[2,20]bithienyl-5-yl)-1H-pyrazole (14)6i and 4-bromo-3,5-
dimethyl-1-(50-methyl-[2,20]bithienyl-5-yl)-1H-pyrazole (15)6j in
good yields. The structure of 14 was confirmed unambiguously by
X-ray diffraction (Fig. 1).8 Crystals of 14 suitable for X-ray analysis
were obtained by slow crystallization from a mixture of petroleum
ether/dichloromethane. The bithiophene fragment is characterized
by a transoid conformation. The N(1)–C(2A) and C(5A)–C(5B) bond
lengths [1.408(4) and 1.445(4) Å] indicate that a conjugated system
is present over the whole molecule. There is a weak shortened inter-
molecular contact N(2)ꢀ ꢀ ꢀH(C6B) (2.65(5) Å) in the crystal structure.
It should be noted that there are no asymmetric atoms in the struc-
ture and the molecules coincide with their mirror antipodes due to
the planar conformation, nevertheless, the crystal structure is chiral
(the space group is P212121).
The useful oligomer 166k was prepared by treatment of 5,50-
diiodo-2,20-bithiophene with 2 equiv of 3,5-dimethylpyrazole in
good yield (87%). Also 2,6-diiodo-dithieno[3,2-b;20,30-d]thiophene
was converted into 2,6-(3,5-dimethylpyrazolyl)-dithieno[3,2-
b;20,30-d]thiophene (17)6l in a poor 20% yield.
In summary, a mild and inexpensive method for the arylation of
five-membered N-heterocycles was developed. Introduction of
pyrazole moieties to an
a-thiophene chain opens an easy route
to prepare more complicated oligomers.

5054
P. Arsenyan et al. / Tetrahedron Letters 51 (2010) 5052–5055
Table 2
CuF2-catalyzed N-arylation of heterocycles with halothiophenes
Entry
Ar-Hal
Het-NH
Product
Yield (%)
65
N
N
I
N
S
S
N
1
N
H
10
Br
I
I
N
S
S
S
N
2
3
5
37
59
36
N
H
Br
11
N
N
N
S
N
H
12
N
N
Br
Br
N
N
S
S
N
N
H
13
S
N
I
S
S
N
N
N
H
6
7
S
67
71
14
Br
S
N
I
S
S
N
N
N
Br
S
N
H
15
S
I
I
S
S
N
N
N
N
S
N
N
8
87
20
H
16
S
S
N
N
I
I
N
N
10
N
H
S
S
S
S
17
Figure 1. ORTEP molecular structure of 3,5-dimethyl-1-(50-methyl-[2,20]bithienyl-5-yl)-1H-pyrazole (14).

P. Arsenyan et al. / Tetrahedron Letters 51 (2010) 5052–5055
5055
(400 MHz, CDCl3/TMS) d (ppm): 2.27 (6H, s, 2 ꢂ CH3); 2.34 (6H, s, 2 ꢂ CH3);
5.97 (2H, s, 2 ꢂ ArH); 6.83 (2H, s, 2 ꢂ ArH). 13C NMR (100.6 MHz, CDCl3/TMS) d
(ppm): 12.2, 13.5, 107.4, 118.3, 138.5, 140.9, 150.0.; (i) 3,5-dimethyl-1-(50-
methyl-[2,20]bithienyl-5-yl)-1H-pyrazole (14) 1H NMR (400 MHz, CDCl3/TMS) d
(ppm): 2.28 (3H, s, CH3); 2.37 (3H, s, CH3); 2.48 (3H, d, CH3, J = 1.2 Hz); 5.97 (1H,
s, ArH); 6.64–6.68 (1H, m, ArH); 6.80 (1H, d, ArH, J = 4.0 Hz); 6.92 (1H, d, ArH,
J = 3.4 Hz); 6.94 (1H, d, ArH, J = 3.4 Hz). 13C NMR (100.6 MHz, CDCl3/TMS) d
(ppm): 12.4, 13.5, 15.3, 107.5, 118.9, 121.1, 123.6, 125.9, 134.2, 134.5, 139.4,
140.1, 140.4, 149.8.; (j) 4-bromo-3,5-dimethyl-1-(50-methyl-[2,20]bithienyl-5-
yl)-1H-pyrazole (15) 1H NMR (400 MHz, CDCl3/TMS) d (ppm): 2.21 (3H, s, CH3);
2.30 (3H, s, CH3); 2.41 (3H, s, CH3); 6.57–6.61 (1H, m, ArH); 6.76 (1H, d, ArH,
J = 4.0 Hz); 6.85 (1H, d, ArH, J = 4.0 Hz); 6.88 (1H, d, ArH, J = 3.6 Hz). 13C NMR
(100.6 MHz, CDCl3/TMS) d (ppm): 11.7, 12.4, 15.4, 96.9, 120.1, 121.1, 123.9,
126.0, 134.2, 135.1, 138.5, 139.4, 139.8, 148.4.; (k) 5,50-(3,5-dimethylpyrazol-1-
yl)-2,20-bithiophene (16) mp = 208–210 °C. 1H NMR (400 MHz, CDCl3/TMS) d
(ppm): 2.28 (6H, s, 2 ꢂ CH3); 2.38 (6H, s, 2 ꢂ CH3), 5.98 (2H, s, 2 ꢂ ArH); 6.82
(2H, d, 2 ꢂ ArH, J = 4.0 Hz); 6.99 (2H, d, 2 ꢂ ArH, J = 4.0 Hz). 13C NMR
(100.6 MHz, CDCl3/TMS) d (ppm): 12.5, 13.5, 107.7, 118.6, 121.9, 133.0, 140.4,
References and notes
1. (a) Cozzi, P.; Carganico, G.; Fusar, D.; Grossoni, M.; Menichincheri, M.; Pinciroli,
V.; Tonani, R.; Vaghi, F.; Savlati, P. J. Med. Chem. 1993, 36, 2964–2972; (b) Ley, S.
V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42, 5400–5449.
2. Kiyomori, A.; Marcoux, J.-F.; Buchwald, S. L. Tetrahedron Lett. 1999, 40, 2657–
2660.
3. (a) Antilla, J. C.; Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 11684–
11688; (b) Antilla, J. C.; Baskin, J. M.; Barder, T. E.; Buchwald, S. L. J. Org. Chem.
2004, 69, 5578–5587.
4. Lakshmi Kantam, M.; Venkanna, G. T.; Sridar, C.; Shiva Kumar, K. B. Tetrahedron
Lett. 2006, 47, 3897–3899.
5. (a) Arsenyan, P.; Paegle, E.; Belyakov, S. Tetrahedron Lett. 2010, 51, 205–208; (b)
Arsenyan, P.; Pudova, O.; Popelis, J.; Lukevics, E. Tetrahedron Lett. 2004, 45,
3109–3111; (c) Lukevics, E.; Arsenyan, P.; Belyakov, S.; Pudova, O. Chem.
Heterocycl. Compd. 2002, 38, 632–645; (d) Lukevics, E.; Arsenyan, P.; Pudova, O.
Main Group Met. Chem. 2002, 25, 135–154; (e) Arsenyan, P.; Pudova, O.; Lukevics,
E. Tetrahedron Lett. 2002, 43, 4817–4819; (f) Lukevics, E.; Barbarella, G.;
Arsenyan, P.; Shestakova, I.; Belyakov, S.; Popelis, J.; Pudova, O. J. Organomet.
Chem. 2001, 636, 26–30; (g) Lukevics, E.; Arsenyan, P.; Belyakov, S.; Popelis, J.;
Pudova, O. Tetrahedron Lett. 2001, 42, 2039–2041.
6. General procedure: A mixture of 4-iodoanisole (0.2 mmol), N-heterocycle (0.22
mmol), copper(II) fluoride (0.1 mmol), 1,10-phenanthroline (0.1 mmol), and
K2CO3 (0.6 mmol) in dry DMF was heated at 140 °C for 72 h. The reaction
mixture was poured into EtOAc, washed with brine, and dried over MgSO4. Pure
product was isolated by column chromatography on silica gel using petroleum
ether/EtOAc as eluent. The structures of all the compounds were confirmed by
1H (400 MHz, CDCl3) and 13C (100.6 MHz, CDCl3) NMR (a) Alberola, A.; Bleye, L.
C.; Gonzalez-Ortega, A.; Sadaba, M. L.; Sanudo, M. C. Heterocycles 2001, 55, 331–
352; (b) Zhu, L.; Li, G.; Luo, L.; Guo, P.; Lan, J.; You, J. J. Org. Chem. 2009, 74, 2200–
2202; (c) 1-(4-methoxyphenyl)-4-bromo-3,5-dimethylpyrazole (5) Oil. 1H NMR
(400 MHz, CDCl3/TMS) d (ppm): 2.23 (3H, s, CH3); 2.27 (3H, s, CH3); 3.83 (3H, s,
CH3); 6.92–6.97 (2H, m, 2 ꢂ ArH); 7.24–7.30 (2H, m, 2 ꢂ ArH). 13C NMR
(100.6 MHz, CDCl3/TMS) d (ppm): 11.5, 12.3, 55.5, 95.6, 114.2, 126.3, 132.9,
137.6, 147.1, 159.1.; (d) Tang, B.-X.; Guo, S.-M.; Zhang, M.-B.; Li, J.-H. Synthesis
2008, 1707–1716; (e) ethyl 5-benzyloxy-1-(4-methoxyphenyl)indol-2-
ylcarboxylate (9)1 H NMR (400 MHz, CDCl3/TMS) d (ppm): 1.26 (3H, t, CH3,
J = 7.4 Hz); 3.89 (3H, s, CH3); 4.23 (2H, q, CH2, J = 7.4 Hz); 5.12 (2H, s, CH2); 6.98–
7.07 (4H, m, 4(ArH); 7.18–7.21 (1H, m, ArH); 7.22–7.28 (2H, m, 2(ArH); 7.31–
7.44 (4H, m, 4(ArH); 7.45–7.51 (2H, m, 2(ArH).13 C NMR (100.6 MHz, CDCl3/
TMS) (ppm): 14.2, 55.4, 60.4, 70.7, 103.9, 110.5, 112.5, 114.1, 117.3, 126.1, 127.5,
127.8, 128.5, 129.0, 129.4, 131.3, 136.6, 137.3, 154.1, 159.1, 161.2.; f 4-bromo-
3,5-dimethyl-1-(thien-2-yl)-1H-pyrazole (11) Oil. 1H NMR (400 MHz, CDCl3/
TMS) d (ppm): 2.28 (3H, s, CH3); 2.34 (3H, s, CH3); 6.95–7.00 (2H, m, 2 ꢂ ArH);
7.18 (1H, dd, ArH, J = 2.2 Hz, J = 5.0 Hz). 13C NMR (100.6 MHz, CDCl3/TMS) d
(ppm): 11.6, 12.4, 96.6, 120.3, 122.9, 125.6, 138.7, 141.7, 148.3.; (g) Chen, W.;
Zhang, Y.; Zhu, L.; Lan, J.; Xie, R.; You, J. J. Am. Chem. Soc 2007, 129, 13879–
13886; (h) 2,5-di(3,5-dimethylpyrazol-1-yl)thiophene (13) Oil. 1H NMR
141.0,
150.0.;
(l)
2,6-(3,5-dimethylpyrazol-1-yl)-dithieno[3,2-b;20,30-
(ppm): 2.22 (6H, s,
d]thiophene (17) 1H NMR (400 MHz, CDCl3/TMS)
d
2 ꢂ CH3); 2.34 (6H, s, 2 ꢂ CH3); 5.94 (2H, s, 2 ꢂ ArH); 7.11 (2H, s, 2 ꢂ ArH).
13C NMR (100.6 MHz, CDCl3/TMS) d (ppm): 12.4, 13.5, 107.9, 112.6, 127.0, 137.6,
140.7, 141.9, 150.2.
7. (a) Sexias de Melo, J.; Pina, J.; Rodrigues, L. M.; Becker, R. S. J. Photochem.
Photobiol. A: Chem. 2008, 194, 67–75; (b) Di Corato, R.; Piacenza, P.; Musarò, M.;
Buonsanti, R.; Cozzoli, P.; Zambianchi, M.; Barbarella, G.; Cingolani, R.; Manna,
L.; Pellegrino, T. Macromol. Biosci. 2009, 9, 952–958; (c) Reese, C.; Roberts, M. E.;
Parkin, S. E.; Bao, Z. Adv. Mater. 2009, 21, 3678–3681; (d) Mori, A.; Sekiguchi, A.;
Masui, K.; Shimada, T.; Horie, M.; Osakada, K.; Kawamoto, M.; Ikeda, T. J. Am.
Chem. Soc. 2003, 125, 1700–1701.
8. Diffraction data were collected at ꢃ20 °C on a Nonius KappaCCD diffractometer
using graphite monochromated Mo K
a radiation (k = 0.71073 Å). The crystal
structure of 14 was solved by direct methods9a and refined by full-matrix least
squares.9b All non-hydrogen atoms were refined in anisotropic approximation;
all
a = 5.8002(1), b = 14.6023(4), c = 15.8278(5) Å; V = 1340.56(6) Å3, Z = 4,
= 0.38 mmꢃ1, Dcalcd = 1.360 g cmꢃ3; space group is P212121. A total of 2234
reflection intensities were collected; for structure refinement, 1934
independent reflections with I >3 (I) were used. The final R-factor is 0.042.
H atoms were refined isotropically. Crystal data for 14: orthorhombic;
l
r
For further details, see the crystallographic data for 14 deposited with the
Cambridge Crystallographic Data Centre as Supplementary Publication Number
CCDC 760725. Copies of the data can be obtained, free of charge, on application
to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK.
9. (a) Altomare, A.; Burla, M.; Camalli, M.; Cascarano, G.; Giacovazzo, C.;
Guagliardi, A.; Moliterni, A.; Spagna, R. J. Appl. Crystallogr. 1999, 32, 115–119;
(b) Mackay, S.; Dong, W.; Edwards, C.; Henderson, A.; Gilmore, C. J.; Stewart, N.;
Shankland, K.; Donald, A. maXus, Integrated Crystallography Software, Bruker-
Nonius and University of Glasgow, 2003.