Application of Piperazine-Derived Hydrazone Linkers for Alkylation of Solid-Phase Immobilized Ketones

Abstract

The preparation and application of three new solid supports with piperazine-derived hydrazine anchoring groups are described. The supports were used for immobilization of ketones. The ketones: cyclohexanone, 4-tert-butylcyclohexanone, 3-pentanone and tropinone, which were bound to polymers in the form of their hydrazones, were deprotonated with LDA and alkylated with propyl iodide or benzyl bromide. The resulting alkylated products were cleaved off the solid support on treatment with trifluoroacetic acid in dichloromethane. Linkers with 6- and 3-carbon atom spacers gave better results than the simple N-aminopiperazine linker.

alkylations - hydrazones - ketones - lithiation - solid-phase synthesis

References

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11

CAUTION: N-Nitrosoamines are potentially carcinogenic. Therefore we recommend special caution during handling and preparation.

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13

Procedure for Reduction of Nitrosoamine to Hydrazine on Polymeric Support: The resin 14 (2.175 g, 2 mmol, theoretical loading 0.95 mmol/g, prepared from Novabiochem Merrifield polymer HL, 1.10 mmol/g, 1% DVB, 200-400 mesh), swollen in anhyd THF (15 mL) was heated with LAH (0.46 g, 12 mmol) under argon atmosphere to 55 ºC for 48 h. Then the reaction mixture was treated carefully with NH₃ aq and KOH aq to decompose the grey suspension of LAH. The resulting white precipitate was dissolved and removed by washing with 2 M HCl aq. The resin was washed with a mixture of concd HCl and THF (4.5:5.5, 2 × 10 mL), repeatedly with THF, methanol, dichloromethane followed by 10% (v/v) solution of triethylamine in dichloromethane (3 × 8 mL, under argon) and repeatedly with methanol and dichloromethane. The resulting resin was dried under high vacuum to constant mass (2.130 g, 93%).

14

Microanalytical data (% of N) did not always show accurately the loading of hydrazine or hydrazone on the resins. Therefore a better method based on gravimetric measurement was developed. [15] The results of loading determinations based on Et₃N·HCl and t-butylcyclo-hexanone were usually in good agreement.

Procedure for Determination of Loading of Hydrazine on Polymeric Support:

15a

Based on amine hydrochloride: The resin 17 (0.500 g) was washed twice with a solution of aq concd HCl in THF (v/v 4.5:5.5) and washed repeatedly with THF, methanol and dichloromethane. Then the resin was washed three times with a 10% (v/v) solution of triethylamine in dichloromethane and repeatedly with methanol and dichloromethane. The combined amine solutions were concentrated and the residue was dried under vacuum to give white crystalline solid, Et₃N·HCl (0.122 g, 0.59 mmol/g).

15b

Based on 4-t-butylcycohexanone(20): The resin 17 (0.500 g) was swollen in a solution of 20 (0.462 g, 3 mmol) in THF (5 mL) and heated in the presence of molecular sieves 4 Å under reflux over 12 h. Then the sieves were removed with tweezers and the resin was washed repeatedly with THF and ether. Then the resin was washed three times with 10% (v/v) solution of TFA in dichloromethane and repeatedly with methanol and dichloromethane. The combined acid solutions were washed with aq K₂CO₃, dried, and concentrated under moderate vacuum to give crystalline solid (0.045 g, 0.58 mmol/g).

16

Typical Procedure for the Alkylation of a Ketone on Solid-Phase: The resin 17 (0.500 g, 0.295 mmol, 0.59 mmol/g, prepared from Novabiochem Merrifield polymer HL, 1.10 mmol/g, 1% DVB, 200-400 mesh) loaded with cyclohexanone was washed under argon atmosphere with anhyd THF (2 × 3 mL). The resin was cooled to 0 ºC for
10 min and treated with a solution of LDA in THF (3.60 mL, 0.98 M, 12 equiv) for 6 h. The resulting deep red resin was filtered under argon, cooled to -78 ºC, and treated with solution of propyl iodide (0.591 g, 0.34 mL, 3.55 mmol) in THF (3 mL). The reaction mixture was allowed to warm up slowly to r.t. over 14 h and was quenched with water (1 mL). The resin was washed repeatedly with THF, ether, dichloro-methane and twice with 10% (v/v) TFA in dichloromethane followed by methanol and dichloromethane. The combined acidic solutions were washed with aq K₂CO₃, dried (MgSO₄) and concentrated to give 2-propylcyclohexanone (0.038 g, 92%).

17

Structures of all new compounds were confirmed by spectrometric analyses and structures of polymers by IR and gel-phase ¹³C NMR spectroscopy.