A Scalable Protocol for the Regioselective Alkylation of 2-Methylcyclohexane-1,3-dione with Unactivated sp³ Electrophiles

Abstract

A method for the C-selective alkylation of 2-methylcyclohexane-1,3-dione with unactivated sp³ electrophiles is accomplished via alkylation and subsequent deprotection of the derived ketodimethyl hydrazones. The present method provides a high-yielding entry to dialkyl cycloalkanones that cannot be accessed via direct alkylation of 2-methylcyclohexane-1,3-dione. The title reaction may be useful in the scalable preparation of terpene and steroidal building blocks in the arena of natural product synthesis.

Key words

alkylation - regioselectivity - hydrazones - ketones - alkyl halides - steroids - terpenoids

• References and Notes


For illustrative examples of the use of 2.2-dialkylcyclohexanediones in target-oriented synthesis, see:
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• 9 Typical Procedure for Alkylation of 4KH (30% dispersion in oil, 0.20 g, 1.50 mmol, 1.50 equiv) was washed free of oil with PE and suspended in anhydrous THF (3.0 mL). The suspension was transferred to a flame-dried, 10 mL round-bottomed flask under an atmosphere of N₂, and the suspension was cooled to –78 °C. Hydrazone 4 (0.25 g, 1.50 mmol, 1.50 equiv) was dissolved in THF (1.0 mL) and added dropwise to the KH suspension. The resulting solution was warmed to 0 °C and stirred 4.5 h. The reaction was recooled to –78 °C, and 1-iodooctane (0.18 mL, 1.00 mmol, 1.00 equiv) was added dropwise. The mixture was allowed to stir overnight, allowing the reaction to slowly warm to r.t. as the dry ice bath evaporated. After 14 h, the reaction was quenched via addition of sat. NH₄Cl aq (4.0 mL), and the mixture was partitioned in a separatory funnel. The organic layer was separated, and the aqueous layer was extracted with Et₂O (3 × 10 mL). The combined organic extracts were washed with brine (10 mL), dried with MgSO₄ and concentrated in vacuo. The product was purified via flash chromatography (hexanes–EtOAc, 80:20 to 70:30) to afford the product ketohydrazone (0.25 g, 91% yield) as a yellow oil.
• 10 Typical Procedure for Hydrazone Hydrolysis (Method 1)A 10 mL round-bottomed flask was charged with Cu(OAc)₂·H₂O (0.20 g, 1.00 mmol, 2.00 equiv) and H₂O (3.3 mL), and the solution was allowed to stir until complete dissolution of Cu(OAc)₂·H₂O was observed, typically 2 min. The intermediate ketohydrazone derived from alkylation of 4 with 1-iodooctane (0.14 g, 0.50 mmol, 1.00 equiv) was dissolved in THF (3.3 mL) and added to the Cu(OAc)₂·H₂O solution. The resulting reaction mixture was allowed to stir until complete conversion of the starting material was observed by TLC analysis, typically 12 h. The reaction mixture was concentrated on a rotary evaporator to remove THF, and the remaining solution was quenched with sat. NH₄Cl aq (5 mL) and diluted with CH₂Cl₂ (5 mL). The mixture was partitioned in a separatory funnel, the organic layer was separated, and the aqueous layer was extracted with CH₂Cl₂ (3 × 10 mL). The combined organic extracts were dried with Na₂SO₄ and concentrated in vacuo. The product was purified via flash chromatography (hexanes–EtOAc, 90:10 to 80:20) to afford diketone 5a (0.12 g, 99% yield) as a yellow oil.
• 11 Typical Procedure for Hydrazone Hydrolysis (Method 2)A 20 mL scintillation vial was charged with acetone (2.0 mL) and Oxone (1.20 g, 2.00 mmol, 4.00 equiv) with magnetic stirring. The intermediate ketohydrazone derived from alkylation of 4 with 2-iodopropane (0.11 g, 0.50 mmol, 1.00 equiv) was dissolved in acetone (0.7 mL) and transferred to the Oxone solution at r.t., producing a white suspension. The resulting mixture was stirred 2 h, whereupon the solution was concentrated on a rotary evaporator to remove the acetone. The remaining solution was diluted with H₂O (5 mL) and transferred to a separatory funnel. The aqueous layer was extracted with EtOAc (2 × 7 mL) and CH₂Cl₂ (2 × 7 mL), and the combined organic extracts were dried with MgSO₄ and concentrated in vacuo. The product was purified via flash chromatography (hexanes–EtOAc, 90:10 to 80:20) to afford diketone 5h (0.051 g, 65% yield) as a yellow oil.