Palladium catalyzed cross-coupling reaction of 5-tributylstannyl-4- fluoropyrazole

Article abstract of DOI:10.1039/b419329f

The palladium catalyzed cross-coupling reactions of aryl iodides and 5-tributylstannyl-4-fluoropyrazole prepared from fluoro(tributylstannyl) acetylene proceeded smoothly giving the corresponding 5-aryl-4-fluoropyrazole in good yields. The Royal Society of Chemistry 2005.

Full text of DOI:10.1039/b419329f

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Palladium catalyzed cross-coupling reaction of 5-tributylstannyl-4-
fluoropyrazole{
Takeshi Hanamoto,*a Yukinori Koga,a Eisaku Kido,a Toshio Kawanami,b Hiroshi Furunob and Junji Inanagab
Received (in Cambridge, UK) 4th January 2005, Accepted 15th February 2005
First published as an Advance Article on the web 1st March 2005
DOI: 10.1039/b419329f
We next examined the palladium catalyzed cross-coupling
reactions of 3 with 4-iodoacetophenone (5) as an aryl iodide
under various conditions (Table 1). After several attempts, the
optimal yield of the cross-coupling product was obtained (entry 9)
when a mixture of 3, 5 (1.1 equiv.) and [Pd(PPh3)4] (5 mol%) in
DMSO was heated at 100 uC for 3 h.§ To our delight, the adduct
(6a) gave single crystals suitable for X-ray crystallographic
analysis." A crystal packing drawing of 6a is shown in Fig. 1.
This X-ray analysis provided unambiguous proof of the regio-
chemistry of the fluorinated pyrazole. The features of the reaction
are as follows: the use of DMSO was essential to the success of the
reaction, to obtain the adduct in high yield.8 Addition of CuTC
and/or LiCl as additives to the reaction mixture remarkably
improved the yield (entries 6 and 8), however, did not always do so
for aryl iodides bearing an electron-donating group (vide infra). In
the presence of these additives, the higher reaction temperature
(100 uC) resulted in the decomposition of 3 to decrease the yield.
From the viewpoint of the catalytic activity, PdCl2(PPh3)2 was
slightly inferior to Pd(PPh3)4.
The palladium catalyzed cross-coupling reactions of aryl
iodides and 5-tributylstannyl-4-fluoropyrazole prepared from
fluoro(tributylstannyl)acetylene proceeded smoothly giving the
corresponding 5-aryl-4-fluoropyrazole in good yields.
Fluorinated heterocyclic compounds play an important role in
various fields such as agrochemicals, pharmaceuticals, polymers
and dyes.1 For example celecoxib, as a famous anti-inflammatory
agent containing both fluorine and a pyrazole ring, represents
both above categories.2 These circumstances suggest that it is still
of importance to develop effective methods for the synthesis of
fluorinated azaheterocyclic compounds. Among them, function-
alized pyrazoles bearing fluorine(s) would be suitable candidates
for the facile preparation of their derivatives. On the basis of this
idea, we have recently reported the palladium catalyzed cross-
coupling reactions of 5-tributylstannyl-4-trifluoromethylpyrazole.3
Our attention was next paid to the synthesis of the corresponding
ring-fluorinated pyrazoles due to the lack of efficient routes for the
preparation of the 4-fluoropyrazole family.4 We report herein the
first preparation of 5-tributylstannyl-4-fluoropyrazole as a func-
tionalized 4-fluoropyrazole and its cross-coupling reaction.
Under the optimal conditions except for the reaction time, the
cross-coupling reaction of 3 with a variety of aryl halides pro-
ceeded smoothly to give the corresponding pyrazoles in good to
high yields (Table 2). Although slight scattering in yields was
observed on varying the positions of the substituents on the
aromatic rings, aryl iodides bearing not only an electron-
withdrawing group but also an electron-donating group were
suitable for the reaction. The corresponding aryl bromide was
We planned the preparation of 5-tributylstannyl-4-fluoro-
pyrazole using the 1,3-dipolar cycloaddition of diazomethane
and fluoro(tributylstannyl)acetylene according to
a slightly
modified version of our procedure for that of 5-tributylstannyl-
4-trifluoromethylpyrazole.3 The requisite acetylene was prepared
in situ from 1,1-difluoroethylene (1) and chlorotributylstannane
(nBu3SnCl) using 2 equivalents of sec-BuLi at a low temperature.5
The GC-MS spectrometric analysis of the reaction mixture at
270 uC gave a single peak that corresponded to fluoro(tributyl-
stannyl)acetylene (2). However, attempts to isolate 2 invariably
resulted in its decomposition probably due to its thermal
instability. Consequently, to the resulting solution containing 2
was successively added an excess of ethereal diazomethane solu-
tion at 230 uC to give the corresponding 5-tributylstannyl-4-
fluoropyrazole (3) in 98% yield, exclusively (Scheme 1).{
The regiochemistry of this pyrazole (3) was determined as
follows. After this isomer was transformed to the corresponding
non-stannylated pyrazole (Scheme 2), the structural assignment
was performed on the basis of the comparison of the correspond-
ing 19F NMR chemical shift value in the literature.6 The
regiochemistry of the reaction can be explained in terms of
HOMO–LUMO interactions as discussed in the literature.7
Scheme 1 One pot synthesis of 5-tributylstannyl-4-fluoropyrazole (3).
{ Electronic supplementary information (ESI) available: 1H NMR and
19F NMR data for 4, 6b–6g and 7. See http://www.rsc.org/suppdata/cc/b4/
b419329f/
Scheme 2 Destannylation of 3.
*hanamoto@cc.saga-u.ac.jp
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Table 1 Cross-coupling reaction of 3 with 4-iodoacetophenone (5) under various conditionsa
Entry
CuTCb (mol%)
LiCl (mol%)
Time (h)
Solvent
Temperature (uC)
Yieldc (%)
1
2
3
4
5
6
7
8
9
5
5
5
—
5
5
5
—
—
—
—
—
20
—
100
20
—
20
—
—
89
18
37
13
39
17
18
2
DMF
DMF
DMF
DMF
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
25
80
25
100
25
25
25
100
100
100
44
Trace
0
40
28
100
45
100
100(91)d
84
3
2
10e
a
b
All reactions were conducted using 3 (1 equiv.) with 4-iodoacetophenone (5) (1.1 equiv.) in the presence of Pd(PPh3)4. Cu(I) thiophene-2-
c
d
e
carboxylate. GC yield. Isolated yield in parentheses. PdCl2(PPh3)2 was used instead of Pd(PPh3)4.
Scheme 3 Iodination of 3.
almost less effective (entry 7). Although one hetero-aromatic
bromide afforded the corresponding adduct in a low yield, the
adduct was unstable and its decomposition occurred during work-
up (entry 8).
Finally, in addition to the cross-coupling reaction, introduction
of iodine to 3 was also examined (Scheme 3). The reaction
proceeded smoothly to give the corresponding 4-fluoro-5-iodopyr-
azole (7) in 95% yield.
Fig. 1 Crystal packing of 6a. Hydrogen bonds are shown by dotted lines.
Table 2 Cross-coupling reaction of 3 with various aryl halidesa
In summary, we have demonstrated the facile synthesis of 3,
via the 1,3-dipolar cycloaddition reaction of 2 with diazomethane,
in one step and its cross-coupling reaction for the construction
of 4-fluorinated pyrazole derivatives. Further studies on their
synthetic utility are progress in our laboratory.
We greatly thank F-Tech Co., Ltd for
1,1-difluoroethylene.
a
gift of
Entry Ar–X
Time (h) Product Yieldb (%)
Takeshi Hanamoto,*a Yukinori Koga,a Eisaku Kido,a
Toshio Kawanami,b Hiroshi Furunob and Junji Inanagab
aDepartment of Chemistry and Applied Chemistry, Saga University,
Honjyo-machi 1, Saga 840-8502, Japan.
1
2
3
4
5
6
7
8
9
a
2,4-Me2C6H3I
2-ClC6H4I
3
16
16
3
9
5
6b
6c
6d
6e
6f
6g
6a
—
—
94
89
83
74
59
84
2-(CO2Me)C6H4I
3-(MeO)C6H4I
4-(MeO)C6H4I
4-(NO2)C6H4I
4-AcC6H4Br
E-mail: hanamoto@cc.saga-u.ac.jp; Fax: +81-952-28-8548;
Tel: +81-952-28-8704
bInstitute for Materials Chemistry and Engineering (IMCE), Kyushu
University, Hakozaki, Higashi-ku, Fukuoka 812-8581, Japan
2
2
2
trace
35c
0
2-Br-5-(NO2)pyridine
5-Br-pyrimidine
Notes and references
All reactions were conducted using 3 (1 equiv.) with aryl halides
{ Preparation of 3: a 100 mL two-neck flask equipped with a magnetic stir
bar, a stopcock and a three-way stopcock, was charged with 18 mL of
THF under argon. To the stirred mixture was added sec-BuLi (0.96 M in
cyclohexane solution, 10.0 mL, 9.6 mmol) dropwise via syringe at 278 uC.
(1.1 y 1.3 equiv.) in the presence of 5 mol% of Pd(PPh3)4 in DMSO
b
c
at 100 uC. Isolated yield. GC yield. This product gradually
decomposed during work-up.
2042 | Chem. Commun., 2005, 2041–2043
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procedures on F2 for all reductions (SHELXL9711). All hydrogen atoms
were positioned geometrically and refined as riding. CCDC 258756. See
http://www.rsc.org/suppdata/cc/b4/b419329f/ for crystallographic data in
.cif or other electronic format.
After this mixture had been stirred for an additional 10 min, the solution
was cooled to 2105 uC in a liquid N2–ethanol bath. At this temperature,
argon was replaced with 1,1-difluoroethylene (balloon). The mixture was
gradually warmed to 270 uC. Chlorotributylstannane (Bu3SnCl, 1.20 mL,
4.43 mmol) was added dropwise to the solution by syringe. After the
addition had been completed, the reaction mixture was allowed to warm to
230 uC. To the resulting reaction mixture was added an excess of ethereal
diazomethane solution and the mixture was gradually warmed to room
temperature. After hexane (10 mL) and water (20 mL) were successively
added to the solution, the organic layer was separated from the mixture.
The resulting aqueous layer was extracted with hexane–ether (3:1) three
times. After the combined organic layer was dried over sodium sulfate, and
filtered through a short silica gel column (ether as an eluent), the eluate was
concentrated in vacuo. The resulting oily residue was purified by silica gel
chromatography (hexane–ethyl acetate, 3:1) to give the desired product (3)
as a colorless oil (1.63 g, 98%): nmax (neat)/cm21 3167; dH(CDCl3) 1.00 (9H,
t, J 7.3 Hz), 1.04–1.24 (6H, m), 1.24–1.39 (6H, m), 1.44–1.68 (6H, m), 7.46
(1H, d, J 5.1 Hz), 9.97 (1H, s); dF(CDCl3) 2176.25 (1F, s); GC-MS m/z 318
[86, M+ 2 57(Bu)], 317 (100); Anal. calcd for C15H29FN2Sn: C, 48.03; H,
7.79; N, 7.47%. Found: C, 48.06; H, 7.68; N, 7.38%.
§ Preparation of 6a: to a solution of 3 (117.1 mg, 0.312 mmol) and
4-iodoacetophenone (85.0 mg, 0.345 mmol) in DMSO (1 mL) was added
Pd(PPh3)4 (18.1 mg, 5 mol%), and the mixture was heated to 100 uC. After
being stirred for 3 h, the resulting mixture was quenched with ethyl acetate
and water and extracted with ethyl acetate. After the usual work-up of an
organostannane experiment,9 the residue was purified by silica gel
chromatography (hexane–ethyl acetate, 1:1) to give 57.7 mg of 6a as a
white solid in 91% yield: mp 159.2–160.8 uC; nmax (neat)/cm21 3158, 1668;
dH(CDCl3) 2.64 (3H, s), 7.55 (1H, d, J 4.2 Hz), 7.91 (2H, d, J 8.4 Hz), 8.02
(2H, d, J 8.4 Hz), 10.4 (1H, s); dF(CDCl3) 2176.18 (1F, d, J 4.2 Hz); GC-
MS m/z 204 (37, M+), 189 (100); Anal. calcd for C11H9FN2O: C, 64.70; H,
4.44; N, 13.72%. Found: C, 64.60; H, 4.56; N, 13.57%.
1 T. Hiyama, in Organofluorine Compounds, ed. H. Yamamoto, Springer
Verlag, New York, 2000; Chemistry of Organic Fluorine Compounds II,
ed. M. Hudlicky and A. E. Pavlath, ACS Monograph 187, Washington,
DC, 1995.
2 T. D. Penning, J. J. Talley, S. R. Bertenshaw, J. S. Carter, P. W. Collins,
S. Doctor, M. J. Graneto, L. F. Lee, J. W. Malecha, J. M. Miyashiro,
R. S. Rogers, D. J. Rogier, S. S. Yu, G. D. Anderson, E. G. Burton,
J. N. Cogburn, S. A. Gregory, C. M. Koboldt, W. E. Perkins, K. Seibert,
A. W. Veenhuizen, Y. Y. Zhang and P. C. Isakson, J. Med. Chem.,
1997, 40, 1347.
3 T. Hanamoto, Y. Hakoshima and M. Egashira, Tetrahedron Lett.,
2004, 45, 7573.
4 For recent references, see: Q. Zhang and L. Lu, Tetrahedron Lett., 2000,
41, 8545; J. Ichikawa, M. Kobayashi, Y. Noda, N. Yokota, K. Amano
and T. Minami, J. Org. Chem., 1996, 61, 2763; H. Yamanaka,
T. Takekawa, K. Morita, T. Ishihara and J. T. Gupton, Tetrahedron
Lett., 1996, 37, 1829; X. Shi, T. Ishihara, H. Yamanaka and
J. T. Gupton, Tetrahedron Lett., 1995, 36, 1527; K. Funabiki,
T. Ohtsuki, T. Ishihara and H. Yamanaka, Chem. Lett., 1995, 239;
H. Molines and C. Wakselman, J. Org. Chem., 1989, 54, 5618.
5 T. Hanamoto, Y. Koga, T. Kawanami, H. Furuno and J. Inanaga,
Angew. Chem. Int. Ed., 2004, 43, 3582.
6 C. Reichardt and K. Halbritter, Justus Liebigs Ann. Chem., 1975, 470.
7 Y. Kobayashi, T. Yamashita, K. Takahashi, H. Kuroda and
I. Kumadaki, Chem. Pharm. Bull., 1984, 32, 4402; I. Fleming, Frontier
Orbitals and Organic Chemical Reactions, John Wiley & Sons, Ltd.,
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J. Am. Chem. Soc., 1973, 95, 7301.
" Crystal data for 6a: (C11H9FN2O?H2O): M 5 222.22, T 5 93(2) K,
¯
˚
triclinic, space group P1, a 5 8.329(15), b 5 11.137(17), c 5 11.87(3) A,
3
˚
8 X. Han, B. M. Stoltz and E. J. Corey, J. Am. Chem. Soc., 1999, 121,
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10 G. M. Sheldrick, SHELXS-97, Program for solution of crystal structures,
University of Go¨ttingen, Germany, 1997.
a 5 76.62(7)u, b 5 73.46(7)u, c 5 82.32(7)u, V 5 1024(3) A , Z 5 4,
Dx 5 1.441 mg m23, m 5 0.113 mm21, l 5 0.71075 A, hmax 5 27.48u,
˚
11589 measured reflection, 4612 independent reflections, 308 refined
parameters, GOF 5 1.019, R[F2 . 2s(F2)] 5 0.0778, wR(F2) 5 0.2160. The
intensity data were collected on a Rigaku RAXIS-RAPID diffractometer.
The structure was solved by direct methods (SHELXS9710) and the non-
hydrogen atoms were refined anisotropically by full-matrix least-squares
11 G. M. Sheldrick, SHELXL-97, Program for refinement of crystal
structures, University of Go¨ttingen, Germany, 1997.
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Chem. Commun., 2005, 2041–2043 | 2043