Bromination benzylic

One type of o-aminobenzyl anion synthon is a mixed Cu/Zn reagent which can be prepared from o-toluidines by / i.s-trimethylsilylation on nitrogen, benzylic bromination and reaction with Zn and CuCN[l]. Reaction of these reagents with acyl halides gives 2-substituted indoles. 

Halogenation (Section 11 12) Free radical halo genation of alkylbenzenes is highly selective for substitution at the benzylic position In the exam pie shown elemental bromine was used Alterna Lively N bromosuccinimide is a convenient re agent for benzylic bromination... 

Replacement of the proton on nitrogen in succinimide by bromine gives N bromo succinimide a reagent used for allylic and benzylic brominations (Sections 10 4 and 1112)... 

Allylicor benzylic bromination or chlonnalion with N bromosuccinimide (NBS) or NCS... 

Benzylic bromination is a more commonly used laboratory procedure than chlorination and is typically caiiied out under conditions of photochemical initiation. 

As we saw when discussing allylic bromination in Section 10.4, A-bromosuccin-imide (NBS) is a convenient free-radical brominating agent. Benzylic brominations with NBS are nonnally perfonned in carbon tetrachloride as the solvent in the presence of peroxides, which are added as initiators. As the exanple illustrates, free-radical bromination is selective for substitution of benzylic hydrogens. 

The chain propagation step consists of a reaction of allylic radical 3 with a bromine molecule to give the allylic bromide 2 and a bromine radical. The intermediate allylic radical 3 is stabilized by delocalization of the unpaired electron due to resonance (see below). A similar stabilizing effect due to resonance is also possible for benzylic radicals a benzylic bromination of appropriately substituted aromatic substrates is therefore possible, and proceeds in good yields. 

As mentioned in an earlier section (cf. Chapter 1, Section III), allylic positions are subject to attack by free radicals resulting in the formation of stable allyl radicals. A-Bromosuccinimide (NBS) in the presence of free-radical initiators liberates bromine radicals and initiates a chain reaction bromination sequence by the abstraction of allylic or benzylic hydrogens. Since NBS is also conveniently handled, and since it is unreactive toward a variety of other functional groups, it is usually the reagent of choice for allylic or benzylic brominations (7). 

The mechanism of benzylic bromination is similar to that discussed in Section 10.4 for allylic bromination of alkenes. Abstraction of a benzylic hydrogen atom generates an intermediate benzylic radical, which reacts with Br2 to yield product and a Br- radical that cycles back into the reaction to carry on the chain. The Br2 necessary for reaction with the benzylic radical is produced by a concurrent reaction of HBr with NBS. 

Benzylic bromination of aikylbenzene side chain (Section 16.9)... 

SIDE-CHAIN BROMINATION OF AROMATIC COMPOUNDS Benzylic bromination of arenes... 

Avramoff et al. have already reported that the reaction of hydrocarbons such as toluene with tetramethylammonium tribromide (TMA Br3) in benzene, in the presence of benzoyl peroxide at room temperature gave benzylic bromination products (ref. 21). However, TMA Br3 is not easy to handle in comparison with the stable BTMA Br3 because of its hydroscopic character. Furthermore, as shown in their literature, a large excess of TMA Br3 is necessary to brominate arenes. 

The same principle can be applied to chlorinations and iodinations (ref. 2) as well as to the benzylic bromination of toluenes and related substrates as intermediates to benzaldehydes and benzoic acids (ref. 6). 

The Wittig reaction can bo used for the double bond and with benzylic bromination In mind wc prefer phosphonium salt (15), bromide (16), and hence available acid (17) as starting materials. 

The accessibility of ethyl-substituted stabilizer precursors suggests benzylic bromination with N-bromosuccinimide followed by base-catalyzed dehydrobromination. Tertiary amines were found to be particularly effective in the syntheses described in this paper. 

Et3N-3HF as a fluorinating agent [285, 286] or with other reagents [475, 476], Benzylic brominations with N-bromosuccinimide in the presence of a radical initiator have been investigated by van Koten [287]. 

EBrIB ethyl-2-bromoisobutyrate. PEBr l-(bromoethyl) benzene, PECl l-(chloroethyl) benzene, BzBr benzyl bromine, MBrP Methyl-2-bromopro-pionate, MCIP methyl 2-chloropropionate, MClAc methyl chloroacetate... 

The difference in the reactivity of benzylic versus aromatic halogens makes it possible to reduce the former ones preferentially. Lithium aluminum hydride replaced only the benzylic bromine by hydrogen in 2-bromomethyl-3-chloro-naphthalene (yield 75%) [540]. Sodium borohydride in diglyme reduces, as a rule, benzylic halides but not aromatic halides (except for some iodo derivatives) [505, 541]. Lithium aluminum hydride hydrogenolyzes benzyl halides and aryl bromides and iodides. Aryl chlorides and especially fluorides are quite resistant [540,542], However, in polyfluorinated aromatics, because of the very low electron density of the ring, even fluorine was replaced by hydrogen using lithium aluminum hydride [543]. 

Notes Used for allylic and benzylic brominations (Wohl-Zieeler Reaction). With moist DMSO the reagent is useful for bromohydrin formation, providing trans addition of bromine and water. Can brominate alpha to carbonyl in carbonyl (carboxyl)-containing compounds. With DMF useful for aromatic bromination of activated aromatic rings, such as phenols, aromatic ethers, aniline derivatives and activated heterocyclic compounds. For similar chemistry, see also NBA, N-Bromoacetamide. 

The o-Amb isomer 33 has been prepared from methyl 2-methylbenzoate (30) by benzylic bromination to give 31, followed by ammonia substitution and hydrolysis of the resulting phthalimidine 32 (Scheme 10)J6L79 ... 

A critical step in a synthesis of the benzoquinone antibiotic sarubicin A (5) is addition of a methyl nucleophile to the aldehyde group of 2. Reaction with CH3MgBr is very slow at low temperatures and the yield and stereoselectivity are low. In contrast, methyltriisopropoxytitanium reacts with 2 to give the desired triol 3 in 80% yield. Oxidative cyclization of 3 to 4 was carried out in two steps benzylic bromination followed by silver-catalyzed ring closure.5... 

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