Side-chain bromination, radical

Fig. 6 High p,T operation for the radical side-chain bromination of m-nitro toluene in a micro-mixer-reactor setup. The large increase in operational temperature increases conversion at good selectivities, which tend to decline slightly with temperature. The two-fold substituted product, m-nitro toluene benzal bromide, is formed in larger amounts at temperatures above 200°C (IMM, unpublished results)...

Tanko, J. M. Blackert, J. F. Free-Radical Side-Chain Bromination of... 

The selectivity of free-radical side-chain bromination of toluene derivatives using A-bromosuccinimide and leading to mono- and dibromo-substituted toluenes has been studied in different solvents [577]. Surprisingly, yields and seleetivities are much better in solvents such as methyl formate and dichloromethane than in the more commonly used tetrachloromethane. 

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)-... 

Like radical side-chain bromination, side-chain chlorination by S02C12 and a peroxide occurs mainly on the a-carbon atom ethylbenzene gives mainly (l-chloroethyl)benzene cumol gives 90% of the a- and 10% of the /9-chloro product. Chlorine enters the jS-position of terf-butylbenzene. o- and p-Nitro-toluene cannot be converted into the corresponding benzyl chlorides by S02C12 and a peroxide.419... 

Dehalogenation. The NBS-mediated radical side-chain bromination of (V,(V-di-ierf-butoxycarbonyl-protected phenylalanine, tyrosine, histidine, or tryptophan and subsequent treatment with AgNOs in acetone provide the frans-oxazolidinones predominantly, which are then converted to the 8-hydroxy amino acid derivatives in excellent overall yield. a-Bromo esters can be transformed to nitrate esters by treatment with AgNOs in acetonitrile. The subsequent oxidation with NaOAc/DMSO gives the corresponding glyoxylate esters. This strategy has been successfully applied into the total synthesis of macrocyclic (+)-brefeldin... 

In addition to the selective oxidation reactions above, a number of other free-radical reactions are summarized herein. Tanko and Blackert (267,268) report the free-radical side-chain bromination of toluene and ethylbenzene in SCCO2 using bromide radicals initiated photochemically from molecular bromine. They report the production of the corresponding benzylic bromides in high yield with selectivities essentially identical to that observed in a conventional chlorinated... 

JM Tanko, JF Blackert. Free-radical side-chain bromination of alkylaromatics in supercritical carbon dioxide. Science 263 203-205, 1994. 

Side-chain bromination at the benzylic position occurs when an alkylbenzene is treated with /V-bromosuccinimide (NBS). For example, propylbenzene gives (l-bromopropyl)benzene in 97% yield on reaction tvith NBS in the presence of benzoyl peroxide, (PhC02)2f as a radical initiator. Bromination occurs exclusively in the benzylic position and does not give a mixture of products. 

Thirtyfold increase in scale of a published method [1] for radical-initiated side-chain bromination of the acid in carbon tetrachloride led to violent reflux and eruption of the flask contents through the condenser [2],... 

Side-chain bromination of methylthiophenes with NBS is a facile reaction (63AHC(l)l). The results are better if the reactive ring positions are blocked or deactivated by suitable -I, -M substituents. Both mono- and di-bromination are possible (Scheme 98). It has been shown that molecular bromine can also be used for side-chain bromination the reaction is carried out in the presence of a radical catalyst (azobisisobutyronitrile) by the action of light. Depending on the substrate, one, two or three bromine atoms may be... 

Side-chain halogenation is illustrated also by the bromination of p-nitrotoluene (Expt 6.28). The radical mechanism with molecular bromine is similar to that of chlorination above N-bromosuccinimide has also found use as a side-chain brominating reagent and its application is described in Expts 6.119 and 6.152. 

Conversion of pyrazinones into bromopyrazines is known (82MI2), as is side-chain bromination, particularly when NBS is used under conditions conducive to radical formation. Thus, 2-ethyl-3-methylpyrazine was converted into the l -bromoethyl derivative (72JOC511). 

Side-chain brominated amino acid derivatives have been exploited in stereo-controlled syntheses of dehydro, cyclopropyl and hydroxy amino acids [39-41], The biochemical hydroxylation of amino acids often involves radical oxidation, where the regioselectivity is analogous to that of bromination. Consequently bromination followed by hydrolysis provides a convenient method for synthesis of the natural products [41], Alternatively, dimethyldioxirane has been used for the direct synthesis of y-hydroxyleucine derivatives through oxygen atom insertion into the yC-H bond [42],... 

Allylic bromination by NBS can be applied with success not only to olefins but also to <%,/ -unsaturated ketones, carboxylic esters, nitriles, and lactones. Radical-formers must be added when NBS is used for allylic bromination of conjugated dienes, for side-chain bromination of aromatic or heterocyclic compounds (see p. 198), or for replacement of tertiary hydrogen atoms next to a C=C bond. 

Radical side-chain halogenation competes with ionic nuclear halogenation for aromatic compounds that carry alkyl substituents. For radical side-chain chlorination or bromination the solvent used, if any, should be apolar (CS2 or CC14 benzene is less suitable). 

Side-chain bromination of alkylthiophenes. Alkylthiophenes are bromi-nated in the side chain by NBS or by bromine under free-radical conditions (hv, azobisisobutyronitrile). One, two, or three bromines can be introduced before ring bromination competes. 

Bromination of alkyl heterocycles with NBS can often give rise to substitution in the side-chain or the nucleus or both. When the reaction was applied to 1,7-dimethoxy-3-methylxanthone, the site of attack depended on the concentration of radical initiator the tendency to side-chain bromination increased with molar ratio of benzoyl peroxide. Reaction of manganese(III) acetate with... 

Meyers and Tavares also investigated radical bromination as a means to effect net oxidation of activated oxazolines. They found these reaction conditions were acceptable for preparing 2-alkyl-4-oxazolecarboxylic acid esters only if the 2-alkyl group was methyl or primary, i.e., 65 Rj = R2 = H or Rj = n-C4, R2 = H. However, these conditions failed completely if the 2-alkyl group was secondary, e.g., isopropyl or cyclohexyl. In these cases, the desired oxazole 65 was isolated in <1% yield. Instead, the sole product was 66, the result of oxidation with concomitant side chain bromination (Scheme 1.20, Table 1.1, entries 7 and 8). 

Microwave Reactions. Side chain bromination of mono and dimethyl heteroaromatic and aromatic compounds by a solid phase Al-bromosuccinimide reaction without radical initiator under microwave conditions was developed. The stereoselective synthesis of ( )-/8-arylvinyl bromides by microwave-induced Huns-diecker-t)q)e reaction has also appeared. ... 

In the latter solvent, cavitation probably helps the formation of the actual reagent, AcO Br+. In the absence of a solvent, side-chain bromination occurs, although in modest yield. Even if a radical mechanism appears probable in this case, the reaction was not examined in sufficient detail for an accurate interpretation. In hexane suspension, solid N-halosuccinimide effects ring halogenation preferentially. The acid catalyst, necessary when the mixture is stirred, can be omitted under sonication. The system consisting of alumina-supported cupric bromide is also efficient to achieve the same reactions.i67... 

Alkyl side chains in both pyrazines and quinoxalines are susceptible to halogenation by elemental halogens (28JCS1960, 68TL5931) and under radical conditions with NBS (72JOC511). Thus, bromination of 2-methylquinoxaline with bromine in the presence of sodium acetate... 

Apart from the nuclear bromination observed (Section 2.15.13.1) in the attempted radical bromination of a side-chain methyl group leading to (396), which may or may not have involved radical intermediates, the only other reaction of interest in this section is a light-induced reduction of certain hydroxypyrido[3,4-f)]pyrazines or their 0x0 tautomers analogous to that well-known in the pteridine field (63JCS5156). Related one-electron reduction products of laser photolysis experiments with 1 -deazaflavins have been described (79MI21502). 

Alkyl Side Chains of Aromatic Rings. The preferential position of attack on a side chain is usually the one a to the ring. Both for active radicals such as chlorine and phenyl and for more selective ones such as bromine such attack is faster than that at a primary carbon, but for the active radicals benzylic attack is slower than for tertiary positions, while for the selective ones it is faster. Two or three aryl groups on a carbon activate its hydrogens even more, as would be expected from the resonance involved. These statements can be illustrated by the following abstraction ratios ... 

Also, ferric ion promotes nuclear (ionic) bromination of benzene derivatives at the expense of the radical reaction at the side chain. 

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