Direct Conversion of Aldehydes and Ketones to Allylic Halides by a NbX₅-[3,3] Rearrangement

Abstract

Sequential addition of vinylmagnesium bromide and NbCl₅, or NbBr₅, to a series of aldehydes and ketones directly provides homologated, allylic halides. Transposition of the intermediate vinyl alkoxide is envisaged through a metalo-halo-[3,3] rearrangement with concomitant delivery of the halogen to the terminal carbon. The [3,3] rearrangement is equally effective for the conversion of a propargyllic alcohol to the corresponding allenyl bromide.

niobium pentachloride - niobium pentabromide - alkyl halides - halogenation - rearrangements

References and Notes

For recent applications in synthesis, see:

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1d Mandal AK. Schneekloth JS. Kuramochi K. Crews CM. Org. Lett.  2006,  8:  427 

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2 Stereoelectronic Effects   Kirby AJ. Oxford University Press; Bath: 1998.  Chap. 5.

3 Magid RM. Tetrahedron  1980,  36:  1901 

4 For a recent example, see: Arteaga JF. Domingo V. Quílez del Moral JF. Barrero AF. Org. Lett.  2008,  10:  1723 

5 For a related rearrangement with BBr₃, see: Punna S. Meunier S. Finn MG. Org. Lett.  2004,  6:  2777 

6

A control experiment in which non-1-en-3-ol was treated with vinylmagnesium bromide led only to recovered alcohol establishing that the bromomagnesium alkoxide does not participate in a bromo-[3,3] rearrangement.

7 An elegant and complementary method using TiCl₄ was recently communicated: Fuchter MJ. Levy J.-N. Org. Lett.  2008,  10:  4919 

8 Mechanistic studies indicate that tertiary allylic alcohols afford mainly primary allylic chlorides on treatment with dry HCl although accompanied by significant side products: Kishali N. Polat MF. Altundas R. Kara Y. Helv. Chim. Acta  2008,  91:  67 

Initial reagent screening with high-valent metals identified TiCl₄, ZrCl₄, NbCl₄, and NbCl₅ as being effective. NbCl₅ provided the greatest conversion with the minimal solvent cleavage. For the strong M-O bond energy in this series, see:

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10

Dry NbCl₅ powder was weighed in a glovebox and transferred directly to the reaction flask under a blanket of dry nitrogen.

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12

Distillation provided chloride 4a in 84% yield with trace impurities not previously observed in the crude product. Purification on SiO₂ or alumina resulted in poor mass recovery with considerable modification of the SiO₂ indicating that the reactive electrophile had alkylated the SiO₂ support.

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15

The use of excess KH ensures the absence of a proton source.

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17 NbCl₅ is known to cleave diethyl ether to afford ethyl chloride: Cowley A. Fairbrother F. Scott N. J. Chem. Soc.  1958,  3133 

18

Vinylmagnesium bromide is far superior to vinylmagnesium chloride.

19 The chloride is contaminated by 2-5% of the corresponding bromide which could arise by direct displacement or by rearrangement of the intermediate alkoxide through a bimetallic magnesium-niobium alkoxide: Jain R. Rai AK. Mehrotra RC. Synth. React. Inorg., Met.-Org., Nano-Met. Chem.  1985,  15:  789 

20

Addition-Chlorination-Sulfide Displacement; General Procedure A THF solution of vinylmagnesium bromide (0.7 M solution) was added to a 10 ˚C, THF solution (0.75-0.85 M) of the aldehyde or ketone. After 15 min 1,4-dioxane (4 volumes relative to THF) and solid NbCl₅ (1.2 equiv) were added sequentially. After 10 min the reaction mixture was poured into 2 M HCl, extracted with EtOAc, and the combined organic extract was then washed with brine and dried (Na₂SO₄). A THF solution (0.2 M) of the crude, essentially pure allylic chloride was added to a 10 ˚C, THF suspension of NaH (2.0-2.5 equiv) to which had been added thiophenol (2.0-2.5 equiv). The reaction mixture was allowed to warm to r.t. over 16 h, poured into an aq NaOH soln (2% by weight) and then extracted with EtOAc. The combined organic extract was washed with brine, dried (Na₂SO₄), and concentrated under reduced pressure to furnish an oily residue that was purified by radial chromatography to furnish the pure sulfide.

21

Performing the addition-rearrangement-sulfenylate displacement with piperonal proceeded in 20% yield with the minor reaction components exhibiting spectral data consistent with acetal cleavage.