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

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.

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

References and Notes

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<A NAME="RG23406ST-16">16</A>

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.

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