Bromination Wohl-Ziegler reaction

Solvent-free benzylic bromination (Wohl-Ziegler reaction) of diquinolines 147 in a ball mill with NBS has been reported by Rahman (Scheme 4.41) [27]. For completion of this reaction, 6h of milling with Af-bromosuccinimide (3.5eqniv.) in Retsch MM200 mill was required. Mechanochemical procedure is advantageous over... 

The direct introduction of a halogen atom (usually bromine) by means of V-haloamine (generally iV-bromosuccinimide) in the allyl position is known as the Wohl-Ziegler reaction ... 

Wohl in 1919 reported that A -bromoacetamide (CH CONHBr) induced allylic bromination. " Then iV-bromosuccinimide (30) was described in 1942 by Ziegler and co-workers to be useful in such free radical bromination reactions (equation 41), " and this widely utilized procedure is known as the Wohl-Ziegler reaction. In 1963 the mechanism of the reaction was proposed to involve halogen atoms in the hydrogen abstraction step " " " instead of succinimidyl radicals as had been commonly supposed. The halogen atom mechanism had previously been proposed by Gosselain et al. for reactions of yV-chlorosuccinimide. " ... 

A second general method involves the bromination of alkenes with jY-bromosuccinimide (the Wohl-Ziegler reaction). A radical-chain reaction takes place between A-bromosuccinimide (NBS) and alkenes, which com-... 

The direct introduction of bromine into the allylic position of an alkene using ZV-bromosuccinimide is known as the Wohl-Ziegler reaction. Bromination is carried out in anhydrous reagents (to avoid hydrolysis of the bromoimide), usually boiling carbon tetrachloride or chloroform solution. The progress of the reaction can be followed by the fact that at first the dense N-bromosuccinimide is at the bottom of the flask and is gradually replaced by succinimide, which rises... 

Djerassi, C. Brominations with N-bromosuccinimide and related compounds. The Wohl-Ziegler reaction. Chem. Rev. 1948,43, 271-317. Horner, L., Winkelmann, E. H. Course of substitution. XV. N-Bromosuccinimide-properties and reactions. Angew. Chem. 1959, 71, 349-365. 

Brominations are, in most cases, carried out by methods similar to those for the preparation of chlorine derivatives. Sampey (127) gives a history of the photobromination of benzene and toluene. Davis (123) made a thorough examination of the relative rates of bromination of the olefins, concentrating particularly on ethylene. An unusual method for producing bromine compounds is by the use of bromosuccinimide or related compounds. This method is called the Wohl-Ziegler reaction and causes allylic bromination. It has been the subject of a couple of reviews (124,1 0). 

The bromination of allylic compounds (Wohl-Ziegler reaction) is generally used in the conversion of aUcenes into conjugated dienes, which are obtained from the allylic bromides by base-catalyzed elimination (Scheme 4.22). 

Olefins react with bromine by addition of the latter to the carbon-carbon double bond. In contrast the Wohl-Ziegler bromination reaction using N-bromosuccinimide (NBS) permits the selective substitution of an allylic hydrogen of an olefinic substrate 1 by a bromine atom to yield an allylic bromide 2. 

Bromination of olefines by NBS is also known as Wohl-Ziegler bromination and as already written, the reaction is specific at allylic position and good yields are obtained. 

In the first propagation step of the Wohl-Ziegler bromination, the bromine atom abstracts a hydrogen atom from the allylic position of the alkene and thereby initiates a substitution. This is not the only reaction mode conceivable under these conditions. As an alternative, the bromine atom could react with the C=C double bond and thereby start a radical addition to it (Figure 1.27). Such an addition is indeed observed when cyclohexene is reacted with a Br2/AIBN mixture. 

The difference is that in the Wohl-Ziegler process there is always a much lower Br2 concentration than in the reaction of cyclohexene with bromine itself. Figure 1.27 shows qualitatively how the Br2 concentration controls whether the combined effect of Br/Br2 on cyclohexene is an addition or a substitution. The critical factor is that the addition takes place via a reversible step and the substitution does not. During the addition, a bromocyclohexyl radical forms from cyclohexene and Br in an equilibrium reaction. This radical is intercepted by forming dibromocyclohexane only when a high concentration of Br2 is present. However, if the concentration of Br2 is low, this reaction does not take place. The bromocyclohexyl radical is then produced only in an unproductive equilibrium reaction. In this case, the irreversible substitution therefore determines the course of the reaction. 

A further useful application of SC-CO2 as a reaction medium is the free-radical side-chain bromination of alkylaromatics, replacing conventional solvents such as tetra-chloromethane or chlorofluorohydrocarbons having no abstractable hydrogen atoms [920]. For example, bromination of ethylbenzene in SC-CO2 at 40 °C and 22.9 MPa yields 95 cmol/mol (1-bromoethyl)benzene, with practically the same regioselectivity as obtained in conventional tetrachloromethane as the solvent. Even the classical Wohl-Ziegler bromination of benzylic or allylic substrates using A-bromosuccinimide (NBS) can be conducted in SC-CO2 [920]. Irradiation of a solution of toluene, NBS, and AIBN (as initiator) in SC-CO2 at 40 °C and 17.0 MPa for 4 hours gave (bromomethyl)-... 

The substitution of a hydrogen atom in the benzylic position by a bromine atom on reaction with N-bromosuccinimide in the presence of catalytic amounts of AIBN (2.37) is known as the Wohl-Ziegler process k... 

When this reagent is used, the reaction is known as Wohl-Ziegler bromination. A nonpolar solvent is used, most often CCI4, but the reaction has been done in an ionic liquid. A variation in the reaction used NBS with 5% Yb(OTf>3 and 5%... 

Tetra-p-tolylsilane, prepared via Wurtz-coupling of 4-bromotoluene and SiCU, was brominated with NBS according to a procedure described by Drefahl [13] yielding a mixture of the three- and four-fold benzylic bromides la, lb which can be separated by repeated crystallization from acetone. A more convenient way is to convert the crude mixture in a Michaelis-Arbusow reaction to the phosphonates 2a, 2b and to separate these via chromatography (SiOa/ethyl acetate/ethanol). A second Wohl-Ziegler bromination/Michaelis-Arbusow sequence allows one to transform 2a into the tetrahedral 2b in moderate yield. 

The mechanism of the Wohl-Ziegler bromination involves bromine radicals (and not imidoyl radicals). The radical initiator is homolytically cleaved upon irradiation with heat or light, and it reacts with Bra (which is always present in small quantities in NBS) to generate the Br- radical, which abstracts a hydrogen atom from the allylic (or benzylic) position. The key to the success of the reaction is to maintain a low concentration of Bra so that the addition across the C=C double bond is avoided. The Bra is regenerated by the ionic reaction of NBS with the HBr by-product. 

The research team of J. Tadanier prepared a series of C8-modified 3-deoxy-P-D-manno-2-octulosonic acid analogues as potential inhibitors of CMP-Kdo synthetase. One of the derivatives was prepared from a functionalized olefinic carbohydrate substrate by means of the Wohl-Ziegler bromination. The stereochemistry of the double bond was (Z), however, under the reaction conditions a cis-trans isomerization took place in addition to the bromination at the allylic position (no yield was reported for this step). It is worth noting that the authors did not use a radical initiator for this transformation, the reaction mixture was simply irradiated with a 150W flood lamp. Subsequently the allylic bromide was converted to an allylic azide, which was then subjected to the Staudinger reaction to obtain the corresponding allylic amine. 

Togo, H., Hirai, T. Environmentally-friendly Wohl-Ziegler bromination Ionic-liquid reaction and solvent-free reaction. Synlett 200Z, 702-704. Greenwood, J. R., Vaccarella, G., Capper, H. R., Mewett, K. N., Allan, R. D., Johnston, G. A. R. Theoretical studies on the free-radical bromination of methylpyridazines in the synthesis of novel heterocyclic analogs of neutro-transmitters. THEOCHEM1996, 368, 235-243. Gainsforth, J. L., Klobukowski, M., Tanner, D. D. Structure and Reactions of the Succinimidyl Radical A Density Functional Study. J. Am. Chem. Soc. 1997,119, 3339-3346. 

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