The Mannich Reaction of Hydrazones Amenable to Solid Phase Synthesis: A Powerful Tool for Heterocycle Preparation

Abstract

The Mannich reaction of hydrazones with aldehydes and benzylpiperazine yields functionalised hydrazones, which are efficient azoalkene precursors. When the hydrazonopiperazines are thus heated with various isocyanides in the presence of dibromoethane, 5-aminopyrazoles are cleanly formed. The choice of benzylpiperazine in the Mannich reaction allows a simple extension of this reaction to solid phase chemistry.

Key words

hydrazones - Mannich bases - cycloaddition - solid phase synthesis - heterocycles

References

• 1 Atlan V. Buron C. Elkaim L. Synlett  2000,  489 
• 2 Biere H. Shröder E. Ahrens H. Kapp JF. Bottcher I. Eur. J. Med. Chem.  1982,  27 
• 4 Kiel G. Ried W. Liebigs Ann. Chem.  1957,  605:  167 
• 5 Atlan V. Bienaymé H. El Kaim L. Majee A. Chem. Commun.  2000,  1585 
• 6 Kiel G. Ried W. Liebigs Ann. Chem.  1958,  616:  108 
• 7 Hird NW. Irie K. Nagai K. Tetrahedron Lett.  1997,  7111 

3

Fipronil (CAS No. 120068-37-3) patented by Aventis is one of the leading pesticide for crop and pet protection.

8

A typical procedure is given for the preparation of 5a : From the Related Hydrazone 3: To a 3 M solution of hydrazone in toluene were added 1,2- dibromoethane (2 equiv) and isocyanide derivative (1.2 equiv). The reaction mixture was allowed to reflux until completion (monitored by TLC, 16 h). The excess solvent was evaporated under reduced pressure and the crude product was purified by flash chromatography on silica gel to give 5a as brown crystals in a 63% yield. From Merrifield Resin: To a suspension of the supported piperazine (3.2 g, 4.5 mmol, prepared according to reference 7) in toluene (50 mL), the hydrazone (2.9 g, 4.0 equiv, 18 mmol) and formaldehyde (1.5 mL, 4.0 equiv, 18 mmol, 37% aqueous solution) were added under an inert atmosphere. The mixture was heated at 80 °C for 48 hours to complete the reaction. After cooling the reaction mixture to room temperature, it was washed with toluene, then with dichloromethane and finally with a 1:1 mixture of dichloromethane and toluene. After filtration it was dried overnight under vacuum at 30 °C to give 5.1 g of the supported Mannich base (5.1 g).
To a suspension of the supported Mannich base (3.5 g, 3.8 mmol) in toluene (20 mL) were added 1,2-dibromoethane (1.43 g, 2.0 equiv, 7.6 mmol) and cyclohexylisocyanide (0.87 g, 1.2 equiv, 4.6 mmol). The resulting mixture was stirred at reflux for 12 h to complete the reaction. It was then filtered after cooling at room temperature. The solid was washed with dichloromethane and toluene. The mixed solvents were then evaporated under reduce pressure to give the crude product. Purification by flash chromatography on silica gel afforded the desired product with a global yield of 20%.

1-(5-Cyclohexylamino-1-phenyl-1H-pyrazol-3-yl)-ethanone(5a)
IR: 3268, 2930, 2851, 1683 cm^-1. ¹H NMR (200 MHz, CDCl₃) δ 7.56-7.26 (m, 5 H), 6.00 (s, 1 H), 3.59 (d, J = 6.6 Hz, 1 H), 3.17-3.03 (m, 1 H), 2.58 (s, 1 H), 2.08-0.82 (m, 10 H). ¹³C NMR (50 MHz, CDCl₃) δ 194.7, 151.3, 146.2, 136.0, 129.6, 128.1, 124.5, 86.5, 54.3, 32.9, 25.7, 25.5, 24.6. MS (CI): 302 (M + NH₄ ⁺), 284 (MH⁺). mp 87-89 °C. FABHRMS calcd. For C₁₇H₂₂N₃O (MH⁺) 284.1763, found 284.1758.