Wohl-Ziegler reaction initiators

The synthesis of anastrozole (Scheme 3.3) began with an 8 2 displacement of commercially available 3,5-fc (bromomethyl)toluene (19) using potassium nitrile and a phase-transfer catalyst, tetrabutylammonium bromide (Edwards and Large, 1990). The resulting fcw-nitrile 20 in DMF was then deprotonated with sodium hydride in the presence of excess methyl iodide to give the fc -dimethylated product 21. Subsequently, a Wohl-Ziegler reaction on 21 was carried out using A-bromosuccinamide (NBS), and a catalytic amount of benzoyl peroxide (BPO) as the radical initiator. Finally, an Sn2 displacement of benzyl bromide 22 with sodium triazole in DMF afforded anastrozole (2) as a white solid. 

The formation of oxygen- and carbon-centered radicals by the thermolysis of peroxides or azo compounds is well known. Today, these compounds have been also used as radical initiators. For example, treatment of a CC14 solution of toluene and Af-bromosuccinimide (NBS) in the presence of a catalytic amount of benzoyl peroxide in refluxing conditions gives benzyl bromide in good yield as shown in Scheme 1.5. This is called the Wohl-Ziegler reaction. 

The Wohl-Ziegler reaction is the reaction of an allylic or benzylic substrate with 7V-bromosuccinimide (NBS) under radical initiating conditions to provide the eor-responding allylie or benzylie bromide. Conditions used to promote the radieal reaction are typieally radical initiators, light and/or heat earbon tetrachloride (CCI4) is typieally utilized as the solvent. 

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. 

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 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. 

Allylic bromination of glycals 10 and 18 was investigated under the usual Wohl-Ziegler conditions with /V-bromosuccinimide (NBS/CCLt/reflux) in the presence of azobi-sisobutyronitrile (AIBN) as initiator. Although both bromides were easily formed in this reaction, the nonfluorinated one appeared to be unstable and could not be isolated [70], The parent 10-CF3-16-bromo derivative 22 was also obtained in good yield (72%) (see Scheme 6.12). The compound could be purified by crystallization and stored for several weeks at 0°C. Clearly, the electron-withdrawing character of the CF3 group makes the allyl bromide less labile. 

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