Cross-coupling of 1-aryl-5-bromopyrazoles: Regioselective synthesis of 3,5-disubstituted 1-arylpyrazoles

Article abstract of DOI:10.1016/S0040-4039(00)00704-8

The cross-coupling of 1-aryl-5-bromopyrazoles 4 with alkynes, vinyltins and arylboronic acids promoted by Pd(PPh₃)₄ afforded unsymmetrical 3,5- disubstituted 1-arylpyrazoles 5-8 in excellent yields, 1-Aryl-5- bromopyrazoles 4 were prepared from their corresponding 1-arylpyrazolones 3 with PBr₃ in refluxing acetonitrile. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00704-8

Tetrahedron Letters 41 (2000) 4713±4716
Cross-coupling of 1-aryl-5-bromopyrazoles: regioselective
synthesis of 3,5-disubstituted 1-arylpyrazoles
Xiao-jun Wang,* Jonathan Tan and Karl Grozinger
Department of Chemical Development, Boehringer Ingelheim Pharmaceuticals Inc., Ridge®eld, CT 06877, USA
Received 9 March 2000; revised 18 April 2000; accepted 21 April 2000
Abstract
The cross-coupling of 1-aryl-5-bromopyrazoles 4 with alkynes, vinyltins and arylboronic acids promoted
by Pd(PPh3)4 a€orded unsymmetrical 3,5-disubstituted 1-arylpyrazoles 5-8 in excellent yields. 1-Aryl-5-
bromopyrazoles 4 were prepared from their corresponding 1-arylpyrazolones 3 with PBr3 in re¯uxing
acetonitrile. # 2000 Elsevier Science Ltd. All rights reserved.
Condensation of 1,3-diketones and their equivalent 1,3-dienophilic synthons such as propargylic
ketones with arylhydrazines has been widely used for synthesis of N-arylpyrazoles, often producing
two regioisomers in the case of 3,5-disubstituted pyrazoles.1 Another powerful tool is aromatic
substitution of N-nonsubstituted pyrazoles with activated halogenated aromatics. This method,
however, faces the same regiochemistry issue because pyrazole is an ambident nucleophile.2
Although there are reports on regio-controlled synthesis of pyrazoles, they have had limited
application.3 Because we required a variety of 3,5-disubstituted 1-arylpyrazole, we needed a general
regio-controlled approach to this class of compounds. In this communication, we are pleased to
report that cross-coupling of readily available 1-aryl-5-bromopyrazoles4,5 with terminal alkynes,6
organostannanes7 and arylboronic acids8 gives unsymmetrical 3,5-disubstituted 1-arylpyrazoles
in excellent yields.
1-Aryl-5-bromopyrazoles were prepared as shown in Scheme 1. Pyrazolones 3 were made in
good to excellent yields from condensation of ketoesters 1 with arylhydrazines 2 in re¯uxing
acetic acid using a known method.9 Pyrazolones 3 were then converted to 5-bromopyrazoles 4
with PBr3 in re¯uxing acetonitrile in 70±85% yields.10 Usually, less than 15% of the starting
pyrazolones 3 was recovered from these reactions, and highly soluble 5-bromopyrazoles 4 were
easily taken up into less polar solvents such as a mixture of hexane and ethyl acetate.
The cross coupling of 5-bromopyrazoles 4a±d with terminal acetylenes was conducted in Et3N
as solvent at 70ꢀC, and was promoted by Pd(PPh3)4/CuBr.SMe2. Greater than 90% yield of
* Corresponding author.
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00704-8

4714
Scheme 1.
products 5±8a were isolated as shown in Table 1. Similarly, the Stille reaction of 4a±d with
vinylstannane in THF at re¯ux for 4±6 h led to 5-vinylpyrazoles 5±8b in excellent yields. Similar
result (5±8c, Table 1) was also obtained from the Suzuki coupling between 5-bromopyrazole 4a±d
and arylboronic acids. Actually, the crude coupling products of 4 with acetylenes and arylboronic
acids were clean enough for further elaboration with no need of puri®cation. In an e€ort to prepare
a large quantity of 6b, the coupling of 4b with propargyl alcohol was achieved with only 0.01
mol% PdCl2 (with two equiv. of PPh3) using triethylamine as a base in re¯uxing THF, and 6b
was obtained in quantitative yield. The same low loading of PdCl2/2PPh3 was also e€ective for
the coupling of 4b with phenylboronic acid. These results clearly indicate that the cross coupling
reaction can serve as a general approach for synthesis of unsymmetrical 3,5-disubstituted 1-aryl-
pyrazoles from their corresponding 5-bromopyrazoles.
The following are representative procedures:
1-(4-Chlorophenyl)-3-phenyl-5-bromopyrazole (4c): to a solution of pyrazolone 2c (2.00 g, 7.38
mmol) in acetonitrile (5 mL) was added PBr3 (4.0 mL, 37 mmol) and the mixture was heated to
re¯ux for 72 h. After being cooled to 0ꢀC, the mixture was slowly quenched with ice/water
and extracted with a 5:1 mixture of hexane and ethyl acetate. The extract was dried over MgSO4 and
concentrated. The residue was puri®ed by column chromaꢀtography on silica gel (hexane:acetate,
1
15:1) to give 4c as a white solid (2.10 g, 84%). Mp: 88±89 C. H NMR (400 MHz, CDCl3) 7.86
(d, J=7.0 Hz, 2H), 7.63, 7.52 (ABq, J=9.0 Hz, 4H) 7.47 (dd, J=7.0, 7.5 Hz, 2H), 7.38 (m, 1H),
6.84 (s, 1H). 13C NMR (400 MHz, CDCl3) 153.7, 137.9, 134.7, 132.5, 129.6, 129.2, 129.0, 127.3,
126.1, 114.0, 108.5. MS m/e 333 (MH+). Anal. calcd for C15H10ClBrN2: C, 54.00; H, 3.02; N,
8.40; Cl, 10.63. Found: C, 53.89; H, 2.93; N, 8.38; Cl, 10.77.
The cross-coupling of 4c with alkyne: to a solution of 5-bromopyrazole 4c (300 mg, 0.90 mmol)
in triethylamine (5 mL) was added Pd(PPh3)4 (21 mg, 0.018 mmol) and CuBr.SMe2 (8 mg, 0.036
mmol), followed by 2-methyl-3-butyn-2-ol (0.10 mL, 0.99 mmol). The mixture was heated to
70ꢀC for 1 h and cooled to room temperature. The solid was ®ltered o€ and the ®ltrate was
concentrated. The residue was puri®ed by column chromatography on silica gel (hexane:acetate,
4:1) to give pyrazole 7a (286 mg, 94%). Mp: 112±113ꢀC. H NMR (400 MHz, CDCl3) 7.89 (d,
1
J=7.0 Hz, 2H), 7.83 (d, J=8.5 Hz, 2H) 7.48±7.38 (m, 5H), 6.92 (s, 1H), 1.61 (s, 6H). 13C NMR
(400 MHz, CDCl3) 152.5, 138.7, 133.5, 132.6, 129.3, 129.2, 128.8, 126.2, 125.8, 124.8, 110.5,
110.4, 102.1, 72.0, 66.0. MS m/e 337 (MH+). Anal. calcd for C20H17ClN2O: C, 71.32; H, 5.09; N,
8.32; Cl, 10.53. Found: C, 71.25; H, 5.03; N, 8.23; Cl, 10.80.
The cross-coupling of 4a with vinyl tributyltin: to a solution of 5-bromopyrazole 4a (138 mg,
0.49 mmol) in THF(5 mL) was added Pd(PPh3)4 (21 mg, 0.018 mmol) followed by vinyl tributyltin
(0.16 mL, 0.54 mmol). The mixture was heated to re¯ux for 6 h under N2, it was then quenched

4715
Table 1
Cross couplings of 5-bromopyrazoles 4 with terminal acetylenes, boronic acids and vinyl tins
with saturated KF and extracted with EtOAc. The extract was dried over MgSO4 and concentrated.
The residue was puri®ed by column chromatography on silica gel (hexane:acetate, 10:1) to give
1
pyrazole 5b (103 mg, 92%). H NMR (400 MHz, CDCl3) 8.37, 7.70 (ABq, J=9.0 Hz, 4H), 6.59
(dd, J=17.6, 11.0 Hz, 1H), 6.46 (s, 1H), 5.82 (dd, J=17.6, 1.0 Hz, 1H), 5.47 (dd, J=11.0, 1.0 Hz,
1H), 2.38 (s, 3H). 13C NMR (400 MHz, CDCl3) 151.4, 146.3, 144.9, 142.7, 125.1, 124.8, 124.6,
119.2, 106.8, 13.9. MS m/e 230 (MH+). Anal. calcd for C17H13ClN2: C, 62.87; H, 4.84; N, 18.33.
Found: C, 62.76; H, 4.90; N, 18.15.

4716
The cross-coupling of 4c with arylboronic acids: to a solution of 5-bromopyrazole 4c (200 mg,
0.60 mmol) in THF (5 mL) was added Pd(PPh3)4 (14 mg, 0.012 mmol) and 4-methoxy-
phenylboronic acid (110 mg, 0.7 mmol), followed by 2 M Na2CO3 (1.0 mL, 2.0 mmol). The
mixture was heated to re¯ux for 4 h, and then quenched with water and extracted with EtOAc.
The extract was dried over MgSO4 and concentrated. The residue was puri®ed by column chroma-
tography on silica gel (hexane:acetate, 15:1) to give pyrazole 7c (210 mg, 97%). Mp: 104±105ꢀC
(lit.3c 104±106ꢀC).
Acknowledgements
We wish to thank Dr. John Proudfoot for helpful discussions during the course of this work.
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