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Synlett 2010(4): 602-606  
DOI: 10.1055/s-0029-1218521
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

The Preparation of Substituted Pyrazoles from β,β-Dibromo-enones by a Tandem Condensation/Suzuki-Miyaura Cross-Coupling Process

Sandra Beltrán-Rodil, Michael G. Edwards, David. S. Pugh, Mark Reid, Richard J. K. Taylor*
Department of Chemistry, University of York, Heslington, York YO10 5DD, UK
Fax: +44(1904)434523; e-Mail: rjkt1@york.ac.uk;
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Publication History

Received 28 September 2009
Publication Date:
02 December 2009 (online)

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Abstract

Two consecutive tandem processes are described for the regioselective, two-step synthesis of 1,3,5-trisubstituted pyrazoles from α-hydroxyketones. The first, a tandem MnO2-mediated oxidation/Ramirez olefination reaction, provides a facile route to β,β-dibromo-enones. These valuable 1,3-dicarbonyl synthons can then be converted into 1,3,5-trisubstituted pyrazoles via a second tandem hydrazine condensation/Suzuki-Miyaura cross-coupling reaction. Using these procedures, a range of aryl and alkyl α-hydroxyketones have been transformed regioselectively into 1,3,5-trisubstituted pyrazoles.

Key words

tandem oxidation process - TOP - β,β-dibromo-enones - 1,3,5-trisubstituted pyrazoles - Suzuki-Miyaura

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13

All novel compounds (3b-g, 6d, 6f, 6g and 7d) were fully characterised. For example: 21-(2′,2′-Dibromoethenyl)-3β-methoxy-5-pregnen-20-one (3g): Pale-yellow micro-crystals; mp 113-115 ˚C (MeOH-H2O, 85:15); [α]D ²².5 +45.1 (c 1.00, CHCl3); R f = 0.21 (petrol-Et2O, 1:1); IR (NaCl): 2964, 2937, 2902, 2852, 2828, 1691, 1552, 1454, 1383, 1094, 732, 691 cm-¹; ¹H NMR (400 MHz, CDCl3): δ = 7.25 (s, 1 H), 5.35-5.32 (m, 1 H), 3.34 (s, 3 H), 3.06 (dddd, J = 11.6, 11.6, 4.6, 4.6 Hz, 1 H), 2.55 (dd, J = 8.9, 8.9 Hz, 1 H), 2.39 (ddd, J = 13.2, 4.6, 2.4 Hz, 1 H), 2.32-2.23 (m, 1 H), 2.15 (ddd, J = 13.2, 11.6, 2.8 Hz, 1 H), 1.83-2.04 (m, 4 H), 1.37-1.72 (m, 8 H), 1.13-1.30 (m, 2 H), 1.05 (ddd, J = 13.4, 13.4, 3.4 Hz, 1 H), 0.95-1.02 (m, 1 H, obscured by singlet), 0.99 (s, 3 H), 0.63 (s, 3 H); ¹³C NMR (100 MHz, CDCl3): δ = 197.0, 140.8, 135.0, 121.1, 102.3, 80.2, 64.1, 57.0, 55.6, 50.0, 45.4, 38.8, 38.6, 37.1, 36.9, 31.9, 31.7, 27.9, 24.4, 22.2, 21.0, 19.3, 13.6; MS (ESI): m/z = 499 [M(79Br2) + H]+, 501 [M(79Br8¹Br) + H]+, 503 [M(8¹Br2) + H]+; HRMS-ESI: m/z [M + H]+ calcd for C23H33 79Br2O2: 499.0842; found: 499.0833 (1.8 ppm error); Anal. Calcd for C23H32Br2O2: C, 55.22; H, 6.45. Found: C, 55.04; H, 6.43.

14

In principle, Suzuki-Miyaura coupling could occur before cyclisation in the tandem process, but we believe that this is unlikely for the following reasons: (i) the β,β-dibromo-enone substrates fail to undergo any cross-coupling under the reaction conditions used and (ii) bromopyrazoles have been isolated from several of the tandem processes.

16

Typical procedure for the tandem oxidation-Ramirez olefination: 3,3-Dibromo-1-phenylpropenone (3a): A 100 mL round-bottom flask equipped with an argon inlet, a condenser and a magnetic stirrer, was charged with activated manganese dioxide (1.59 g, 18.36 mmol), phosphonium salt 7 (4.16 g, 8.08 mmol), powdered activated 4 Å molecular sieves (0.10 g) and THF (30 mL). KOt-Bu (0.86 g, 7.71 mmol) was then added to the reaction mixture followed by 2-hydroxyacetophenone [1a; recrystallised from petroleum ether (PE), 0.50 g, 3.67 mmol] as a solution in THF (6 mL). The reaction mixture was then allowed to stir at reflux for 3 h. After cooling to r.t., the mixture was filtered through a pad of Celite® and rinsed with EtOAc (200 mL). The filtrate was concentrated in vacuo and the product was pre-adsorbed on silica and purified by flash column chromatography (PE-Et2O, 9:1) to afford dibromo-enone 3a (0.62 g, 59%) as a yellow oil, R f  = 0.60 (PE-Et2O, 1:1), which solidified upon standing to give a dense yellow solid; mp 44-45 ˚C (Lit.7a 41.5-42.5 ˚C), which was fully characterized.

17

Typical procedure for the tandem condensation/cross-coupling: 1-Methyl-3,5-diphenyl-1H-pyrazole (6a): A 10 mL round-bottom flask equipped with an argon inlet, a condenser and a magnetic stirrer, was charged with 1,1-dimethylhydrazine (20.4 mg, 0.34 mmol) and THF (1 mL). Dibromo-enone 3a (50.0 mg, 0.17 mmol) was then added as a solution in THF (1 mL), followed by Pd(PPh3)4 (9.80 mg, 0.0085 mmol), phenylboronic acid (41.5 mg, 0.34 mmol) and powdered K3PO4 (108.0 mg, 0.51 mmol). After stirring at reflux for 18 h, the reaction mixture was allowed to cool to r.t. and filtered through a small plug of silica gel, rinsing with EtOAc (50 mL). The solvent was removed in vacuo and the oily residue was pre-adsorbed on silica and purified by flash column chromatography (PE-EtOAc, 9:1), to afford
1-methyl-3,5-diphenyl-1H-pyrazole (6a; 30.5 mg, 76%), R f  = 0.40 (PE-Et2O, 1:1), as a pale-yellow solid; mp 58-60 ˚C (Lit.¹8 58-60 ˚C).