Halohydrins rearrangements

PyrazoUne-5-ones. Treatment of 2-bromo-l,3-diphenyl-l,3-propanedione (1) with methylhydrazine in ethanol at room temperature gives l-methyl-3,4-diphenyl-A -pyrazoline-5-one (2) in 56% yield. It is probably formed by a halohydrin rearrangement as indicated. 

The reaction of Grignard reagents with epoxides, at first glance, appears to be an effective method for a two-carbon homoligation. However, there are several competing reactions that limit the use of this method. These deleterious reactions are formation of halohydrins, rearrangements, polymerization of the epoxide, and in asymmetric epoxides, regioselectivity issues. 

Sisti has also explored the potential utility of halohydrin rearrangements for ring expansions. A few examples are outlined. Ring-expanded a-phenyl ketones of product ring size six to nine were prepared in 60-80% yields by the sequence shown in equation (93). ... 

Whereas oc-halohydrinphosphonates are converted into 1,2-epoxyphosphonates by treatment with strong bases, the corresponding P-halohydrins rearrange instantaneously in the presence of aqueous NaHCOj and slowly in water alone to give 1-formylethylphosphonic acid (Scheme 4.35). ... 

Cyclization of halohydrins 0-16 Cyclization of 1,2-diols 0-18 Payne rearrangement of 2,3-epoxy alcohols... 

Results of stereochemical studies with various halohydrins confirm that the oxy-anion attacks the carbon from the opposite side, causing Walden inversion the erythro forms of 3-bromo-2-butanol, stilbene bromohydrin, and chloro malic acid give the trans oxide, and the corresponding threo forms lead to the cis oxides [146]. Furthermore, the frans-halohydrin of cyclohexene reacts 150 times as fast with OH- as the cis compound. Only the reaction of the trans compound yields an epoxide [147] in the reaction of the cis compound, an enol is formed first which then rearranges to the corresponding ketone [148, 149]. 

Oxiranes cannot be prepared directly from 1,2-diols by dehydration. Formation of the oxirane intermediate has been studied in connection with the mechanism of the pinacolic rearrangement. Oxiranes can be prepared stereoselectively from the acetals and ketals of 1,2-diols. D-(+)-2,3-epoxybutane has been obtained from an optically active diol via conversion of the ketal 64 to a halohydrin ester (Eq. 52). ... 

The Durst group has taken advantage of these competing reactions (halohydrin intermediate, Lewis acid-catalyzed rearrangement, and regioselectivity issues) to form... 

The mechanistic outline of carbenoid/carbonyl reactivity follows the paradigm illustrated at the outset of this chapter (Scheme 1 X = halogen). The nucleophilic lithium species adds to the carbonyl compound and suffers elimination to provide the epoxide. Competition from molecular rearrangements emanating from the intermediate halohydrin or the product epoxides is sometimes a problem, particularly with cyclic ketones. Also, the initial adduct frequently fails to cyclize when the reaction is quenched at low temperature, but it is usually a simple matter to effect ring closure by treatment of the halohydrin with mild base in a separate step. 

Rearrangements of halohydrin salts usually require prolonged treatment of ether solutions at ambient temperature or heating in a less polar solvent, but there are some interesting exceptions. The standard conditions consist of formation of the magnesiohalide salt in ether, followed by solvent replacement by benzene and short term reflux. House found that residual ether can significantly influence the course of a reaction, and since this variable appears not to have been carefully controlled in most experiments, comparisons may have limited significance. 

The reaction of cyclohexene oxide with MeMgX was reexamined in 1969, in work which clearly established the importance of the halide. Standard conditions (1 h at 80 C) were employed with 1.4 equiv. of the organometallic, to give the yields listed under equation (83). Only minor amounts of the normal displacement product (200) are formed from the chloride and bromide, and none from the iodide. The iodide and bromide give extensive rearrangement, with the bromide being more selective in the sense that product (198) is expected on the basis of stereoelectronic considerations (backside displacement of halide) from the rra/is-halohydrin. The unusual product from this perspective is (199). It must arise either from the c/s-halohydrin or a process which is not subject to the same stereoelectronic controls, e.g. via a carbenium ion. 

The cleaner reactions of the halohydrins show that these, if formed by anti opening and not subsequently epimerized, cannot account for the product mixtures from the epoxides. House proposed a competing carbenium ion route for both epoxides, leading to the normal pinacol rearrangement (carbenium ion) product, the aldehyde (202). 

In all of these reactions halohydrin salts were implicated as the reactive species, since no rearrangement occurred when the halohydrins were treated with MgBr2. 

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