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Synlett 2006(16): 2581-2584  
DOI: 10.1055/s-2006-950436
LETTER
© Georg Thieme Verlag Stuttgart · New York

Synthesis of 1H-3-Ferrocenyl-1-phenyl-4-substituted Pyrazoles

Milan Joksović, Zoran Ratković, Mirjana Vukićević, Rastko D. Vukićević*
University of Kragujevac, Faculty of Science, Department of Chemistry, R. Domanovića 12, 34000 Kragujevac, Serbia
Fax: +381(34)335040; e-Mail: vuk@kg.ac.yu;
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Publication History

Received 15 July 2006
Publication Date:
22 September 2006 (online)

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Abstract

Synthesis of 1H-3-ferrocenyl-1-phenylpyrazole-4-carboxaldehyde was achieved by condensation of acetylferrocene with phenylhydrazine followed by intramolecular cyclization of the ­hydrazone obtained under Vilsmeier-Haack conditions. Several ­derivatives, such as the corresponding thiosemicarbazone, oxime, imine, alcohol, halide, and primary amine were then prepared by known reactions. Also 1,1′-diacetylferrocene was transformed into the corresponding dipyrazolyl derivative.

Key words

acetylferrocene - 1,1′-diacetylferrocene - phenylhydrazone - Vilsmeier-Haack reagent - pyrazoles

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3-Ferrocenyl-1-phenylpyrazole-4-carboxaldehyde ( 3): To a solution of acetylferrocene (2.28 g, 10.00 mmol) and phenylhydrazine (1.15 g, 10.65 mmol) in EtOH (10 mL) two drops of glacial AcOH were added. The mixture was refluxed for 1.5 h and then cooled to r.t. The precipitate obtained (2.96 g, 93%) was isolated by filtration in vacuo, washed with cold EtOH (5 mL), dried for 1 h in vacuo over CaCl2, and dissolved in DMF (15 mL). Argon was bubbled through the solution for 20 min and then the solution was cooled in an ice bath. To the cold solution POCl3 (2.25 mL, 27.22 mmol) was added dropwise under argon. After 30 min the bath was removed and the reaction mixture was stirred for 18 h at r.t. The mixture was poured into a beaker containing ice (30 g) and H2O (30 mL), the resulting solution was hydrolyzed slowly with Na2CO3 (40 g) dissolved in H2O (100 mL) and stirred for 3 h at r.t. Settled crude aldehyde was filtered off, washed with a large amount of H2O, suspended in H2O (100 mL), and extracted with toluene. After drying (anhyd Na2SO4), the solvent was evaporated and the residue was recrystallized from EtOH yielding 2.99 g of 3 (84% based on the starting acetylferrocene); deep orange crystals; mp 118 °C. IR (KBr): 3123, 3081, 1667, 1540, 1519, 1216, 754, 506 cm-1. 1H NMR (CDCl3): δ = 4.13 (s, 5 H), 4.42 (s, 2 H), 4.94 (s, 2 H), 7.36-7.39 (m, 1 H), 7.45-7.53 (m, 2 H), 7.73-7.77 (m, 2 H), 8.43 (s, 1 H), 10.31 (s, 1 H). 13C NMR (CDCl3): δ = 68.9, 69.6, 69.8, 75.7, 119.5, 122.6, 127.6, 129.6, 131.3, 138.9, 153.7, 184.6.1,1′-Di(4-formyl-1-phenyl)pyrazol-3-ylferrocene ( 12): 1,1′-Diacetyl ferrocene (11; 0.27 g, 10 mmol), DMF (50 mL), phenylhydrazine (2.3 g, 21.3 mmol), and POCl3 (4.5 mL, 54.44 mmol) were reacted according to the procedure described above. After hydrolysis the crude product was dissolved in CHCl3, precipitated with EtOH, and the precipitate was dried in vacuo over CaCl2 giving 0.24 g of 12 (75% based on 1,1′-diacetylferrocene); deep orange powder; mp 241 °C (dec.). IR (KBr): 3130, 3113, 1678, 1540, 1525, 1220, 791, 506 cm-1. 1H NMR [(CD3)2SO]: δ = 4.45 (s, 4 H), 5.08 (s, 4 H), 7.34-7.38 (m, 2 H), 7.42-7.49 (m, 4 H), 7.72-7.76 (m, 4 H), 8.83 (s, 2 H), 9.77 (s, 2 H). 13C NMR [(CD3)2SO]: δ = 69.8, 70.2, 77.6, 119.0, 122.4, 127.3, 129.6, 134.2, 138.5, 150.1, 183.7.3-Ferrocenyl-1-phenylpyrazole-4-carboxaldehyde Thiosemicarbazone ( 4): Aldehyde 3 (0.356 g, 1 mmol), thiosemicarbazide (0.01 g, ca. 1.10 mmol), and one drop of glacial AcOH were dissolved in MeOH (10 mL) and stirred for 6 h at r.t. The volume of the solution was reduced to 1/3 by evaporation allowing the isolation of 0.318 g (74%) of thiosemicarbazone 4 (pure enough for spectral identification); yellow-orange powder; mp 135 °C. IR (KBr): 3414, 3271, 3138, 1598, 1550, 1538, 1220, 754 cm-1. 1H NMR [(CD3)2SO]: δ = 4.19 (s, 5 H), 4.42 (s, 2 H), 4.68 (s, 2 H), 7.30-7.43 (m, 1 H), 7.51-7.60 (m, 2 H), 7.82-7.86 (m, 2 H), 7.92 (br s, 1 H), 8.38 (br s, 1 H), 8.51 (s, 1 H), 9.11 (s, 1 H), 11.56 (br s, 1 H). 13C NMR [(CD3)2SO]: δ = 67.7, 69.0, 69.5, 76.7, 117.3, 118.2, 126.7, 127.1, 129.7, 135.3, 139.1, 150.4, 177.6.3-Ferrocenyl-4-(3-picolyl)iminomethyl-1-phenyl-pyrazole ( 6): Aldehyde 3 (0.356 g, 1 mmol), 3-picolylamine (0.113 g, 1.05 mmol), and one drop of glacial AcOH were mixed in MeOH (10 mL) and the resulting solution was refluxed for 4 h. After cooling the Schiff base was crystal-lized, filtered off, washed with cold MeOH, and dried in vacuo over CaCl2. Yield 0.352 g (79%); red-orange crystals; mp 156-157 °C. IR (KBr): 3104, 3060, 2897, 2824, 1641, 1549, 1504, 1233, 753, 689 cm-1. 1H NMR (CDCl3): δ = 4.10 (s, 5 H), 4.34 (s, 2 H), 4.71 (s, 2 H), 4.82 (s, 2 H), 7.23-7.31 (m, 2 H), 7.39-7.47 (m, 2 H), 7.66-7.74 (m, 3 H), 8.42 (s, 1 H), 8.51 (br s, 1 H), 8.63 (br s, 1 H), 8.79 (s, 1 H). 13C NMR (CDCl3): δ = 62.9, 68.5, 69.0, 69.6, 76.2, 119.0, 119.4, 123.5, 126.8, 127.0, 129.4, 134.7, 135.5, 139.4, 148.6, 149.5, 151.8, 155.6.3-Ferrocenyl-4-hydroxymethyl-1-phenylpyrazole ( 7): Aldehyde 3 (0.356 g, 1 mmol) was suspended in MeOH (20 mL). An excess of NaBH4 (ca. 3 mmol) was added in small portions with stirring at r.t. and stirring was continued for an additional 3 h. The solution was quenched with aq NaOH (20 mL, 20%) and stirred for 3 h. The precipitate obtained was filtered off and recrystallized from EtOH yielding 0.358 g (96%) of 7; orange powder; mp 117-118 °C. IR (KBr): 3438, 3114, 3081, 2917, 1599, 1505, 820, 757, 509 cm-1. 1H NMR (CDCl3): δ = 1.71 (br s, 1 H), 4.13 (s, 5 H), 4.38 (m, 2 H), 4.83 (m, 2 H), 4.92 (s, 2 H), 7.23-7.28 (m, 1 H), 7.40-7.48 (m, 2 H), 7.67-7.71 (m, 2 H) 7.88 (s, 1 H). 13C NMR (CDCl3): δ = 56.2, 67.5, 69.2, 69.9, 76.2, 118.7, 120.4, 126.0, 127.0, 129.4, 139.7, 150.1.4-Chloromethyl-3-ferrocenyl-1-phenylpyrazole ( 8): To a solution of alcohol 7 (0.358 g, 1 mmol) in CH2Cl2 (20 mL), PCl3 (0.1 mL, ca. 1 mmol) was added and the resulting solution was stirred for 2 h at r.t. The mixture was washed with H2O and dried over CaCl2. After evaporation of the solvent 0.284 g (72%) of waxy 8 was isolated. IR (KBr): 3092, 2859, 1598, 1504, 749 cm-1. 1H NMR (CDCl3): δ = 4.14 (s, 5 H), 4.36 (s, 2 H), 4.85 (s, 2 H), 4.88 (s, 2 H), 7.27-7.34 (m, 1 H), 7.42-7.50 (m, 2 H), 7.68-7.72 (m, 2 H), 7.96 (s, 1 H). 13C NMR (CDCl3): δ = 37.1, 67.5, 68.9, 69.5, 76.4, 117.3, 118.8, 126.4, 128.1, 129.4, 139.6, 150.3.4-Azidomethyl-3-ferrocenyl-1-phenylpyrazole ( 9): Chloride 8 (0.378 g, 1 mmol) was stirred overnight with NaN3 (0.130 g, 2 mmol) in DMF (10 mL) at r.t. The mixture was diluted with H2O (50 mL) and extracted with Et2O. After drying over Na2SO4 evaporation of the solvent gave 0.353 g (92%) of waxy azide 9. IR (KBr): 3094, 2092, 1599, 1504, 817, 754, 689 cm-1. 1H NMR (CDCl3): δ = 4.11 (s, 5 H), 4.33 (s, 2 H), 4.46 (s, 2 H), 4.79 (s, 2 H), 7.22-7.29 (m, 1 H), 7.39-7.47 (m, 2 H), 7.67-7.72 (m, 2 H), 7.88 (s, 1 H). 13C NMR (CDCl3): δ = 45.1, 67.7, 68.7, 69.3, 76.4, 114.1, 118.6, 126.2, 127.6, 129.3, 139.6, 150.4.