Hydrodehalogenation of organohalides using ethylpiperidine hypophosphite (EPHP); Alkane

Dr. Ian J. S. Fairlamb ([email protected]),
A contribution from the Fairlamb Group, York *UK)

Chemicals Used
Aqueous 50% w/w hypophosphorous acid (Lancaster), 1-ethylpiperidine (Lancaster), 2,2�-Azoisobutyronitrile (Acros), dry toluene (distilled from calcium hydride), dry dioxane (distilled from sodium/benzophenone ketyl).

Procedure
Synthesis of ethylpiperidine hypophosphite: A solution of aqueous hypophosphorous acid (50% w/w) was dried in vacuo at 50oC (~7 mmHg) with good stirring. After complete removal of the water, the acid was placed under an inert atmosphere (N2) and cooled to 0oC. 1-Ethylpiperidine (1 eqv.) was added to the acid at 0oC, whilst stirring slowly to precipitate out a white salt (hygroscopic). The reaction proceeds in quantitative yield. This salt was used without any further purification as a reagent. Hydrodehalogenation procedure: To a solution of the organohalide (1 eqv.) in dry 1,4-dioxane or toluene (20 mL per mmol of the organohalide), was added EPHP (10 eqv.) and AIBN (0.05 eqv.) in one portion under an inert atmosphere (N2). The reaction mixture was heated to reflux and monitored by TLC, until all starting material had been consumed (3-24 h). The reaction was allowed to cool, then quenched with water and extracted with EtOAc (x4). All the organic extracts were combined, dried (MgSO4) and concentrated in vacuo. The product was purified by column chromatography or by direct recrystallisation.

Author's Comments
EPHP is commercially available but it is relatively expensive given that it may be prepared on large scale (100 g in our hands) very easily. The acid must be thoroughly dried, otherwise the product formed is a viscous oil, which is extremely difficult to dry � this was noticed on larger scale reactions, where trace quantities of water could still be present. In our hands, the salt does not form immediately as described. This seems to be dependant on the scale of the preparation (~20 mins). EPHP must be stored at -20oC in a sealed container/flask. For this hydrodehalogenation reaction, 10 eqv. of EPHP was required, smaller quantities (2-5 eqv.) can be used for more reactive organohalides.

Data
For 3-endo-hydroxy-6-endo-hydroxy-bicyclo[3.2.0]heptane: 1H NMR (CDCl3, 270 MHz) 1.67 (4H, m), 2.09 (1H, d, J=15.1), 2.48 (1H, m), 2.62 (1H, ddd, J=8.9, 13.2, 22.1), 3.10 (1H, m), 3.53 (1H, m), 4.28 (2H, br), 4.51 (1H, d, J=4.3). 13C NMR (CDCl3, 67.9 Mhz) 32.60 (C1), 35.40 (C4), 38.21 (C2), 43.07 (C7), 45.47 (C5), 65.19 (C6), 76.00 (C3). MS (CI) m/z 129 (M+H, 100%)+, 146 (M+NH4, 77%)+, 111 (37%), 93 (24%), 67 (9%). HRMS (CI) calcd for C7H12O2 (M+NH4)+ 146.118104; found 146.117977.

Lead Reference
Barton, D. H. R.; Jang, D. O. Jaszberenyi, J. C. J. Org Chem. 1993, 58, 6838.

Other References
Barton, D. H. R.; Jang, D. O. Jaszberenyi, J. C. Tetrahedron Lett. 1992, 33, 5709.

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