Benzylic position halogenation

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... 

The effects of varying the nature of halogen substituents at C3 and that of the potential leaving group at the benzylic position were then examined. 

Fluorotoluene can be deprotonated in the benzylic position by the superbases, but the halogen appears to offer little activation to the process. 2-Trifluoromethyltoluene is more readily deprotonated, but decomposes by elimination of fluoride even at — 100°C . 

Alkylation of hydroxylamine with primary halides and sulfonates is rarely used nowadays for preparation of A-alkylhydroxylamines due to the competing formation of N,N-dialkylhydroxylamines. A number of older procedures have been reported with low to moderate yields of Al-alkylhydroxylamines. Yet, in many cases the reported low yields can be attributed to workup losses during distillation and crystallization steps rather than to the polyalkylation. Use of excess of hydroxylamine in reactions with primary alkyl halides (e.g. 3) improves the yields of monoalkylation (equation 2). Most of the examples of alkylation of hydroxylamine in good yield involve a substitution of an activated halogen atom at benzylic positions as well as in haloacetamides 4 leading to alkylhydroxylamines such as 5 where dialkylation rates are lower (equation 3). 

The halogen-fluorine exchange with an HF-amine complex allows the transformation of a gem-dichloro goup into a difluoro group. While this reaction is difficult to initiate in nonactivated positions, it is efficient in the benzylic position and in the a position of functional groups (e.g., esters, phosphonates) (Figure 2.10). ... 

The fluorination of allylic231 232 and benzylic positions by halogen replacement using hydrogen fluoride has found very wide interest, since trifluoromethyl groups are highly desired substituents in many applications. Some representative examples are given by the formation of 10,232 II,233- 235 and 12.236... 

Side-Chain Chlorination of Arylalkanes. Alkyl-substituted aromatic compounds can easily be halogenated at the benzylic position with chlorine or bromine.107 108,142 143 a-Monohaloalkylaromatics are usually the main products with both reagents. 

Styrene oxides are preferentially attacked by halides at the benzylic position, especially so under acidic reaction conditions. It has been claimed, however, that in water in the presence of cyclodextrins, styrene oxides react with halides to yield exclusively benzylic alcohols [382], Benzylic alcohols can also be obtained from styrene oxides by treatment with halogens in the presence of pyridines [383],... 

NBS also works well for brominating benzylic positions, next to an aromatic ring (see Problem 6-10). Allylic and benzylic halogenations are discussed in more detail in Chapter 15. 

Alkylbenzenes undergo free-radical halogenation much more easily than alkanes because abstraction of a hydrogen atom at a benzylic position gives a resonance-stabilized benzylic radical. For example, ethylbenzene reacts with chlorine in the presence of light to give cr-chlon >e thy I benzene. Further chlorination can occur to give a dichlorinated product. 

The amide N-H may also be halogenated, oxidized and nitrosated. A -Bromosuccinimide (NBS), like a number of other iV-halo compounds, readily undergoes a radical fission to give a bromine radical. This provides a useful reagent for radical bromination at, for example, allylic or benzylic positions. In the presence of acid, NBS is also a mild source of the halonium ion, which is used for the addition of hypobromous acid (Scheme 3.74) to alkenes or for the bromination of reactive aromatic rings. 

The mechanism for halogenation at the benzylic position resembles other radical halogenation reactions, and so it involves initiation, propagation, and termination. Mechanism 18.10 illustrates the radical bromination of ethylbenzene using Bt2 (h or A). 

The catalytic halogen exchange works especially well in the benzylic position of aromatic compounds, giving access to a variety of industrially important fluori-nated solvents [42, 43] and intermediates [44] (Scheme 2.15). 

In addition to Br2, H-bromosuccinimide is an important reagent for radical chain bromination, especially at allylic and benzylic positions. Mechanistic investigations have established that Br2 is the active halogenating agent under the conditions used... 

Scheme 11.4 illustrates some representative halogenation reactions. The reaction in Entry 1 was conducted by slow addition of bromine to excess 2-methylpentane at 60°C, with irradiation from a tungsten light bulb. The reaction in Entry 2 is a typical benzylic bromination, carried out at 125°C with irradiation from a sun lamp. Entries 3 and 4 are examples of NBS bromination using benzoyl peroxide as the initiator. Entry 3 is interesting in that none of the allylic isomer 2-bromo-3-heptene is found. Entries 5 and 6 are examples of chlorination by f-butyl hypochlorite in which the f-butoxy radical is the chain carrier. Note that in Entry 6, both the primary and secondary allylic products are formed. The reaction in Entry 7 uses sulfuryl chloride as the halogenation reagent. Note that in contrast to chlorination with CI2 (see p. 1021), the reaction shows selectivity for the benzylic position. 

Alkyl-substituted benzenes undergo radical halogenation at the benzylic position (Section 9.5). 

Once a halogen has been placed in the benzylic position, it can be replaced by a nucleophile by means of an Sn2 or an SnI reaction (Section 10.8). A wide variety of substituted benzenes can be prepared this way. 

Regio- and Chemoselective Halogenative Cleavage of Epoxides. DBBS very efficiently and regioselectively cleaves terminal epoxides into 1,2-bromohydrins in 15 min in CH2CI2 (eq 21). With the exception of styrene oxide, the transfer of bromine takes place at the less hindered carbon (terminal carbon). In the case of styrene oxide, the bromine is transferred at benzylic position. ... 

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