Direct conversion of aldehydes and ketones to allylic halides by a NbX 5-[3,3] rearrangement

Article abstract of DOI:10.1055/s-0028-1088222

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. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1088222

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Synlett. Author manuscript; available in PMC 2010 January 1.
Published in final edited form as:
Synlett. 2009 ; 2009(7): 1077–1080. doi:10.1055/s-0028-1088222.
Direct Conversion of Aldehydes and Ketones to Allylic Halides by
a NbX5-[3,3] Rearrangement
*
Fraser F. Fleming , P. C. Ravikumar, and Lihua Yao
Department of Chemistry and Biochemistry, Duquesne University, Pittsburgh, Pennsylvania
15282-1530 Fax: (412) 396 5683
Abstract
Sequential addition of vinylmagnesium bromide and NbCl , or NbBr , to a series of aldehydes and
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ketones directly provides homologated, allylic halides. Transposition of the intermediate vinyl
alkoxide is envisaged through a metalla-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.
Keywords
Niobium pentachloride; niobium pentabromide; alkyl halides; halogenation; rearrangements
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Allylic halides occupy a privaleged position as electrophiles. Activation of the carbon-halogen
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bond by adjacent π electrons dramatically facilitates nucleophilic displacement, allowing
otherwise difficult bond constructions with a diverse range of carbon, heteroatom, and
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organometallic nucleophiles. Allylic halides prepared as intermediates during total syntheses
are typically prepared by halogenation of allylic alcohols. These in turn are often obtained by
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olefination-reduction sequences because the direct “halo-olefination” of carbonyls with
Wittig-type procedures is circumvented by elimination in the reagent.
© Thieme Stuttgart
*E-mail: flemingf@duq.edu.

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A conceptually direct method for converting aldehydes and ketones to allylic halides is through
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a sequenced vinyl addition-metalla-halo-[3,3]-rearrangement (Scheme 1). Addition of
vinylmagnesium bromide to an aldehyde or ketone generates the bromomagnesium alkoxide
,6
2
potentially allowing transmetallation to a more oxophilic metal capable of weakening the
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carbon-oxygen bond for a metalla-halo-[3,3]-rearrangement. Particularly Lewis acidic
halometal alkoxides 3 may cause competitive ionization and halogenation leading to a mixture
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of allylic halide regioisomers whereas metals bearing more nucleophilic halides would favor
the rearranged allylic halide 4.
TiCl effectively promotes this sequence with aromatic aldehydes and with magnesium
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alkoxides derived from deprotonation of allylic alchohols. Results presented below show that
NbCl and NbBr expand the scope of this vinyl addition-metalla-halo-[3,3]-rearrangement to
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include aromatic and aliphatic aldehydes and aromatic and aliphatic ketones. In addition, the
[3,3] rearrangement is equally effective for the conversion of a propargylic alcohol to the
corresponding bromoallene implying a concerted rearrangement in distinction to the related
reactions with TiCl .
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Exploring the viability of a sequenced vinyl addition-metalo-halo-[3,3]-rearrangement initially
focused on identifying an optimal metal and solvent combination. Using the potassium
alkoxide 6 as a prototype, a diverse range of metal chlorides were evaluated for their
effectiveness in providing the allylic chloride 4a (Scheme 2). Screening several oxophilic
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metals identified dry niobium pentachloride in 1,4-dioxane as the optimal combination.
After only 10 minutes at room temperature the alcohol 5 was completely converted to the allylic
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chloride 4a in essentially quantitative yield. H and C NMR analysis of the crude product
indicated the material to be pure.
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The use of niobium pentachloride is particularly intriguing because this strong Lewis acid is
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employed under basic conditions. These conditions contrast with many related reactions in
which transition metal halides exhibit reactivity similar to that of HCl which might be liberated
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by contact of the reagent with moisture. Mechanistically attack of the alkoxide 6 on NbCl
might trigger rearrangement from the niobiate 3a having an expanded coordination sphere
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(Scheme 2). Sequential ionization and chlorination of 3a is a mechanistic possibility,
although the absence of regio- and stereoisomers suggests this to be a minor reaction manifold.
Synthetically the NbCl rearrangement offers the advantage over related phosphonium-based
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reagents in facile isolation of (E)-allylic chlorides simply by an aqueous extraction to remove
inorganic species.
Optimizing the metalo-halo-[3,3]-rearrangement with the allylic alcohol 5 provided a platform
for directly converting aldehyde 1a to the allylic chloride 4a (Scheme 3). Partial ring opening
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of THF by NbCl led to a procedure in which vinylmagnesium bromide was added to a 10
5
°C, THF solution of aldehyde 1a followed by dilution with four volumes of 1,4-dioxane and
addition of solid NbCl (1.2 equiv). After 30 minutes the solution was washed with aqueous
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HCl and concentrated to provide the crude chloride 4a (99%).
The naphthyl-substituted allylic chloride 4a is challenging to purify. Silica-based purification
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methods resulted in significant mass loss suggesting partial alkylation of the solid-phase.
Consequently the crude chloride 4a was redissolved in THF and reacted with sodium
phenylsulfenylate (Scheme 3). The procedure efficiently provided the sulfide 7a ratifying the
efficiency of the niobium rearrangement in generating essentially pure allylic chloride 4a.
Performing the vinyl addition-niobium rearrangement-sulfenylate displacement with a series
of aldehydes efficiently provides the corresponding sulfides (Table 1). Aromatic aldehydes
and ketones smoothly rearrange in the presence of NbCl (Table 1, entries 1-5). The nitrile-
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containing aromatic aldehyde 1e was less reactive toward NbCl but was effectively
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halogenated with NbBr (Table 1, entry 5). Aliphatic aldehydes are converted to the
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corresponding allylic chlorideswith NbCl but greater efficiency is obtained with NbBr (Table
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1, entries 6-7). The aliphatic ketone cyclohexanone reacted sluggishly even with NbBr (Table
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1, entry 8). In each case analysis of the intermediate allylic halide shows complete
rearrangement prior to the sulfenylate displacement.
The metalo-halo-[3,3]-rearrangement is best suited to hydrocarbons. A conjugated aldehyde
(Table 1, entry 4) and a nitrile (Table 1, entry 5) are readily tolerated whereas an acetal is not.
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Effort to further probe the functional group tolerance is in progress.
The metalla-halo-[3,3]-rearrangement is not limited to the addition of vinylmagnesium halide
to aldehydes and ketones. The strategy was extended to halogenation of the propargylic alcohol
8a with the expectation that a concerted rearrangement would favor a haloallene (Scheme 4).
Deprotonating 8a and adding NbCl afforded only a trace of the corresponding chloro allene
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at room temperature with full conversion requiring heating the reaction mixture to reflux. Under
these thermal conditions considerable decomposition occurred whereas substituting NbBr
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triggerred a smooth rearrangement at room temperature. After 2 h the bromoallene 10a was
obtained in 78% yield.
Direct transformation of aldehydes and ketones to the corresponding allylic halides is readily
achieved through a vinyl addition metalo-halo-[3,3]-rearrangement strategy. Sequential
addition of vinylmagnesium bromide and NbCl or NbBr to aromatic and aliphatic aldehydes
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and ketones provides essentially pure allylic chlorides for use in subsequent displacement
reactions. The [3,3] rearrangement is equally effective in the case of a propargyllic alcohol,
which provides the corresponding allenyl bromide. Synthetically, the addition-niobium halide
rearrangement provides an efficient and direct conversion of aldehydes and ketones to allylic
halides in one synthetic operation.
Supplementary Material
Refer to Web version on PubMed Central for supplementary material.
Acknowledgments
Financial support from the National Institutes of Health (2R15AI051352-03) and in part from the National Science
Foundation (0808996 CHE, 0421252 HRMS, and 0614785 for NMR facilities) is gratefully acknowledged.
References
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[PubMed: 15281767]
(6).
(7). An elegant and complementary method using TiCl was recently communicated: Fuchter MJ, Levy
4
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(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.
(9). Initial reagent screening with high valent metals identified TiCl , ZrCl , and NbCl , and NbCl as
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4
4
5
being effective. NbCl provided the greatest conversion with the minimal solvent cleavage. For the
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strong M-O bond energy in this series see: (a) Loock H-P, Simard B, Wallin S, Linton C. J. Chem.
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(16). Gibson VC, Kee TP, Shaw A. Polyhedron 1988;7:2217.
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J. Chem. Soc 1958:3133.
(18).
(19). The chloride is contaminated by 2-5% of the corresponding bromide which could arise by direct
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(20).
(21).
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Scheme 1.
Vinyl Addition-Metalla-Halo-[3,3]-Rearrangement.
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Scheme 2.
Metalla-Halo-[3,3]-Rearrangement.
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Scheme 3.
Direct Vinyl-Addition NbCl Halogenation.
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Scheme 4.
NbBr -Rearrangement to an Allenyl Bromide.
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Table 1
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Sequential Addition-Chlorination-Sulfenylation.
entry
aldehyde
1
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entry
aldehyde
2
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entry
aldehyde
3
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entry
aldehyde
4
5
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entry
aldehyde
6
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entry
aldehyde
7
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entry
aldehyde
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a
Performed with NbBr rather than NbCl .
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