Chemoselectivity, bromination

COMPLETELY REGIO- AND CHEMOSELECTIVE BROMINATION OF fflGHLY CONJUGATED ALKENES... 

Analogous results were obtained for enol ether bromination. The reaction of ring-substituted a-methoxy-styrenes (ref. 12) and ethoxyvinylethers (ref. 10), for example, leads to solvent-incorporated products in which only methanol attacks the carbon atom bearing the ether substituent. A nice application of these high regio-and chemoselectivities is found in the synthesis of optically active 2-alkylalkanoic acids (ref. 13). The key step of this asymmetric synthesis is the regioselective and chemoselective bromination of the enol ether 4 in which the chiral inductor is tartaric acid, one of the alcohol functions of which acts as an internal nucleophile (eqn. 2). 

STEREO-, REGIO- AND CHEMOSELECTIVITY OF BROMINATION OF ETHYLENIC COMPOUNDS... 

Apart from information on stereochemistry, bromine bridging does not provide a priori any rule regarding regio- and chemoselectivity. Therefore, we systematically investigated (ref. 3) these two selectivities in the bromination of ethylenic compounds substituted by a variety of more or less branched alkyl groups (Scheme 4). 

The Markovnikov regioselectivity of the gem-alkenes is associated with a chemoselectivity. in favour of methanol attack, significantly greater than that observed for the other alkenes. If no sodium bromide is added to the reaction medium, no dibromide is observed for this series. Therefore, these alkenes behave as highly conjugated olefins, as regards their regio- and chemo-selectivity. In other words, the bromination intermediates of gem-alkenes resemble P-bromocarbocations, rather than bromonium ions. Theoretical calculations (ref. 8) but not kinetic data (ref. 14) support this conclusion. 

The chemoselectivity of bromination going through bromocarbocations (highly conjugated olefins and also gem-alkenes ) is 100 % in favour of methanol, a nucleophile stronger than bromide ions. However, when the intermediates are bromonium ions, the chemoselectivity is poor. Branched substituents seem to favour the dibromide over the solvent-incorporated adduct, although the bromide ion is considered to be a bulkier nucleophile than methanol. 

The solvent has no influence on the stereoselectivity of bromine addition to alkenes (Rolston and Yates, 1969b), but it could have some effect on the regioselectivity, since this latter depends not only on polar but also on steric effects. Obviously, it modified the chemoselectivity. For example, in acetic acid Rolston and Yates find that 2-butenes give 98% dibromides and 2% solvent-incorporated products whereas, in methanol with 0.2 m NaBr, dibromide is only about 40% and methoxybromide 60%. There are no extensive data, however, on the solvent effects on the regio- and chemoselectivity which would allow reliable predictions. 

Table 6 Chemoselectivity (% solvent-incorporated products) in bromination of styrenes, XC6H4CH = CH2.

To summarize, when the kinetic data predict that only bromonium ions or only bromocarbocations are formed, the bromination products are obtained stereospecifically and regiospecifically, respectively, whatever the solvent. Olefin brominations involving open intermediates lead to more solvent-incorporated products in methanol or acetic acid than those involving bridged ions. This chemoselectivity can be interpreted in terms of the hard and soft acid and base theory (Dubois and Chretien, 1978). Methanol assistance to intermediate formation also plays a role in determining product-selectivity (Ruasse et al, 1991). 

In polyfunctional molecules, the elec-trophore with the least negative reduction potential is selectively cleaved [164]. A bromine atom at a carbon atom a to a carbonyl group is fairly easily reducible therefore, cpe at the potential in which this C— Br bond is reduced proceeds highly chemoselectively (Fig. 35) [164]. 

The sulfone moiety was reductively removed and the TBS ether was cleaved chemoselectively in the presence of a TPS ether to afford a primary alcohol (Scheme 13). The alcohol was transformed into the corresponding bromide that served as alkylating agent for the deprotonated ethyl 2-(di-ethylphosphono)propionate. Bromination and phosphonate alkylation were performed in a one-pot procedure [33]. The TPS protecting group was removed and the alcohol was then oxidized to afford the aldehyde 68 [42]. An intramolecular HWE reaction under Masamune-Roush conditions provided a macrocycle as a mixture of double bond isomers [43]. The ElZ isomers were separated after the reduction of the a, -unsaturated ester to the allylic alcohol 84. Deprotection of the tertiary alcohol and protection of the prima-... 

The first step constitutes a che mo selective radical bromination of the methyl group in quinoline 10 using A-bromosuccinimide (33), leading to compound 34. Here benzoyl peroxide (32) acts as the radical initiator. A rule of thumb for chemoselectivity states that heat and light produce side-chain halogenation, whereas cold and catalysis favor halogenation of the aromatic nucleus. 

The chemoselectivity of olefin bromination is reported84 to occur after the attack of the bromine on the double bond, but the formation of the bromonium ion is the slow step of the reaction. As a consequence, the distribution of products and the selectivity of addition of nucleophiles can hardly be explained by substituent effects (both steric and electronic) bonded to the C=C double bond in a fast step of the reaction. 

Checking for chemoselectivity problems, we might suspect that the amine could be alkylated twice by the very reactive a-bromoketone 74 so it might be better to protect the nitrogen atom with a benzyl group. This can be removed by catalytic hydrogenation. In the laboratory, it proved better to brominate 73 in neutral rather than acidic solution so the final scheme becomes ... 

Hydrogen atoms in the benzylic position can be replaced by elemental bromine as shown. This is not true for hydrogen atoms in the allylic position. The alkene reacts rapidly with molecular bromine via addition and allylic bromination is not observed (Figure 1.25, left). A chemoselective allylic bromination of alkenes succeeds only according to the Wohl-Ziegler process (Figure 1.25, right), that is, with A-bromosuccinimide (NBS). 

Fig. 1.28. Derivation of the kinetic expression for the chemoselectivity of allylic substitution versus bromine addition in the Br /Br2/cyclohex-ene system. The rate constants are defined as in Figure 1.27.

To obtain single or multiple electrophilic brominations chemoselectively, one can simply vary the stoichiometry ... 

Fig. 1.22. Competing chemoselectivities during the reaction of bromine with ort/zo-xylene by a polar mechanism (left) and a radical mechanism (right).

Let us go back to radical brominations (cf. Section. 1.7.3). The bromination of alkyl aromatics takes place completely regioselectively only the benzylic position is bromi-nated. The intermediates are the most stable radicals that are available from alkyl aromatics, namely, benzylic radicals. Refluxing orf/zo-xylene reacts with 2 equiv. of bromine to give one monosubstitution per benzylic position. The same transformation occurs when the reactants are irradiated at room temperature in a 1 2 ratio (Figure 1.22, right). The rule of thumb SSS applies to the reaction conditions that afford these benzylic substitutions chemoselectively. SSS stands for searing heat + sunlight —> side chain substitution. ... 

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