Org Prep Daily

March 16, 2007

(4S)-(4,5-dihydro-4-tert-butyl-2-oxazolyl) ferrocene and (2S)-N-(1-hydroxy-3,3-dimethylbutyl) ferrocenamide

Filed under: Chris Douglas, procedures — milkshake @ 2:10 pm

ferrocenyl-oxazoline.gif

(2S)-N-(1-hydroxy-3,3-dimethylbutyl) ferrocenamide

Ferrocene monocarboxylic acid (16.1 g, 70 mmol, Strem) was suspended in dichloromethane (340 mL) in a 3-neck flask fitted with a nitrogen inlet, septum, and an outgas tube bubbling into a 1L flask Erlenmeyer flask filled with 500 mL of 1 M NaOH. A small amount of DMF (~0.05 mL) was added to the suspension and oxalyl chloride (8.1 mL, 92 mmol) was added to the suspension dropwise over 5 min. The reaction became homogeneous as it was stirred for 1 h. The resulting solution was concentrated and the residue dissolved in dichloromethane (150 mL). The red-orange solution was transferred by cannula to a solution of L-tert-leucinol (8.50 g, 72.5 mmol) and triethylamine (31.7 mL, 220 mmol) in dichloromethane (370 mL) maintained at 0 °C. The reaction mixture was allowed to warm to rt over 3 h and ether (300 mL) was added. The reaction mixture was washed with a solution of NaOH (500 mL, 1M aqueous), dried over MgSO4, filtered through a pad of Celite and concentrated. The orange-brown residue was dissolved in boiling dichloromethane (300 mL) and the solution cooled to –20 °C and maintained for 12 h. The formed orange crystals were collected by vacuum filtration (17.85 g, 54 mmol, 77%). The filtrate was concentrated. The residue was dissolved in boiling dichloromethane (30 mL) and the solution was cooled to –20 °C and maintained for 12 h. A second crop of orange crystals was collected by vacuum filtration (4.94 g, 15 mmol, 21%). The combined crops of crystals (22.55 g, 68.6 mmol, 98%) were identical in all respects to the material prepared by alternative methods. (Ref 1)

Note: Clean your rotovap from any residual HCl after the first concentration. Recommend aspirator vs. diaphragm pump for the first concentration

(4S)-(4,5-dihydro-4-tert-butyl-2-oxazolyl) ferrocene

Methanesulfonyl chloride (MsCl, 8.3 mL, 100 mmol) was added to a solution of (2S)-N-(1-hydroxy-3,3-dimethylbutyl) ferrocenamide (22.55 g, 68.5 mmol) and triethylamine 30 mL (200 mmol) in dichloromethane 0.8L maintained at 0C. The reaction was allowed to warm to RT over 12 h and a solution of saturated aqueous NaHCO3 (0.5L) was added to the reaction mixture. The phases were separated and the aqueous portion was extracted with dichloromethane (2×300 mL) and the combined organic portions were dried over MgSO4 and filtered through a pad of Celite. The filtrate was concentrated and the resulting residue was taken up in boiling hexanes (200 mL) and the solution was decanted, leaving behind a small amount of insoluble brown residue. The resulting homogeneous solution was cooled to –20C and maintained at that temperature for 12 h. The orange needles that formed were collected by vacuum filtration and washed with hexanes (10 mL) to provide the title compound (18.49 g, 59.5 mmol, 87%). The filtrated was concentrated and the resulting residue dissolved in boiling hexanes (20 mL). The solution was cooled to –20 C for 12 h and a second crop of orange needles was collected as above (1.90 g, 6.1 mmol, 9%). The combined crops of needles (20.39 g, 65.6 mmol, 96%) were identical in all respects to the material prepared by alternative methods. (Ref 1)

Ref 1: Sammakia, T.; Latham, H. A.; Schaad, D. R. J. Org. Chem. 1995, 60, 10–11.

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3 Comments »

  1. Why would one use a 3-neck flask, if the solution is supposed to be concetrated right away and only one is actually needed?

    Here’s my procedure: mix everything in 1-neck, drop DMF and put the tube, that’s it.
    The only reason I could think of is if one would really bother with HCl, he could use another neck to blow it away with argon.

    Comment by liquidcarbon — March 16, 2007 @ 5:03 pm

  2. On small scale, I did use a 1-neck, but the HCl outgas got to be too much of a pain on scaleup – the DMF really makes the reaction take off!

    Comment by cjdquest — March 18, 2007 @ 9:20 pm

  3. I liked the second step; I am doing one reaction similar to that (RONa + R’OMs gives ROR’).

    Comment by pmgb — May 17, 2008 @ 1:31 am


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