Benzylic halogenation

Phenyl-[3- (bzw. -4)-chIor-benzyl]- 569 Phenyl-[3- (bzw. -4)-cyan-benzyI]- 569 Phenyl-(n-halogen-benzyl)-. 569 Phenyl-[a-haIogen-3- (bzw. -4)-chlor-benzyI] 569 Phenyl-[a-halogcn-3- (bzw. -4)-cyan-benzyl]-569 Phenyl-(a-halogen-4-nitro-benzyI)- 569 PhenyI-(4-nitro-benzyI)- 569 (1,2,2-TriphenyI-vinyI)-phenyl - 464 Vinyl-phenyl- 633f. 

The phenolic benzyl ether is much more acid labile than the benzyl ethers of serine and threonine. Therefore, O-benzyltyrosine is not adequately stable for multistep SPPS with the Boc/Bzl strategy. To prevent loss of the O-benzyl protection, halogenated benzyl deriva-tivesP have been developed (Scheme 7) the most often used derivative, H-Tyr[Bzl(2,6-Cl2)]-OH, is -5000 times more stable to 50% TFA/CH2CI2 treatment than the unsubstituted benzyl compound. 

Toxophoric Group. —C N —N = C Auxotoxic Group. Halogens, benzyl, etc. 

Oxidative Halogenation. Benzylic bromination and a-iodination of ketones and uracil derivatives can be achieved with CAN as in situ oxidant. 

The classical Ullmann-type synthesis of a bisbenzylisoquinoline involves the direct coupling of a phenolic benzylisoquinoline with a halogenated benzyl-isoquinoline in the presence of copper or one of its salts or oxides. The advantage of this approach is that the two halves of the dimer may be prepared separately as pure enantiomers before the final coupling step. This feature is usually outweighed, however, by low yields in the Ullmann step. 

Functionalized benzylic mesylates containing a halogen atom were also investigated. Reactions of the halogenated benzyl manganese mesylates with acid chlorides, aldehydes, and ketones yielded the corresponding ketone, secondary alcohol, and tertiary alcohol in good to excellent isolated yields as shown in Table 8.11. As mentioned earlier, it is of interest that the mesylates... 

In the absence of catalysts, toluene when treated with chlorine (or bromine) at the boiling point, preferably with exposure to sunlight or other bright light source, undergoes halogenation in the side chain. The entrance of the first chlorine atom, for example, proceeds at a much faster rate than the entrance of the second chlorine atom so that in practice the major portion of the toluene is converted into benzyl chloride before appreciable chlorination of benzyl chloride occurs ... 

It is worth noting here that the results of some other studies of aromatie substitutions, sueh as the Friedel-Crafts benzylation and iso-propylation of alkylbenzenes, and the bromination of alkylbenzenes with bromine, eatalysed by ferrie ehloride, are under suspicion as depending upon slow mixing. As regards halogenation eatalysed by Lewis aeids, positive evidenee to support this eritieism has been obtained. ... 

The comparative ease with which a benzylic hydrogen is abstracted leads to high selectivity m free radical halogenations of alkylbenzenes Thus chlorination of toluene... 

Sections Free radical halogenation and oxidation involve reactions at the benzylic 11 12-11 13 carbon See Table 112... 

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 reactions of benzyl chloride, benzal chloride, and ben zotricbl oride may be divided into two classes (/) reactions of the side chain containing the halogen and (2) reactions of the aromatic ring. 

The chloride is readily available as a by-product of benzyl chloride [100-44-7] production (see Chlorocarbon and chlorohydrocarbons-BENZYL chloride, BENZAL CHLORIDE, AND benzotrichloride). The yield is comparable to the Perkin-based process, but the difficulty associated with removal of trace halogenated impurities makes the resultant cinnamic acid less desirable for many appHcations. 

In many cases, substituents linked to a pyrrole, furan or thiophene ring show similar reactivity to those linked to a benzenoid nucleus. This generalization is not true for amino or hydroxyl groups. Hydroxy compounds exist largely, or entirely, in an alternative nonaromatic tautomeric form. Derivatives of this type show little resemblance in their reactions to anilines or phenols. Thienyl- and especially pyrryl- and furyl-methyl halides show enhanced reactivity compared with benzyl halides because the halogen is made more labile by electron release of the type shown below. Hydroxymethyl and aminomethyl groups on heteroaromatic nuclei are activated to nucleophilic attack by a similar effect. 

Purine, 1,6-dihydro-8,9-dimethyl-6-thioxo-synthesis, 5, 583 Purine, 2,6-dimethoxy-synthesis, 5, 596 Purine, 2,6-dimethoxy-7-methyl-rearrangement, 5, 558 Purine, 2,7-dimethyl-halogenation, 5, 547 Purine, 7,9-dimethyl-UV spectra, 5, 517 Purine, 8,8-dimethyl-synthesis, 5, 580 Purine, 6-dimethylamino-mass spectra, 5, 519 occurrence, 5, 600 Purine, 6-dimethylamino-9-benzyl-alkylation, 5, 531 Purine, 3,7-dimethyl-6,8-dioxo-methylation, 5, 534 Purine, 6,8-dioxo-alkylation, 5, 534... 

Pyran, 4-arylimino- C NMR, 3, 585 Pyran, 4-arylimino-2,6-dimethyl-synthesis, 3, 762 Pyran, 2-aryloxytetrahydro-X-ray studies, 3, 621 Pyran, 4-benzyl-isomerization, 3, 666 Pyran, 3-bromodihydro-synthesis, 3, 769 Pyran, -bromodihydro-halogen-metal exchange with t-butyllithium, 1, 474 Pyran, 2-bromotetrahydro- H NMR, 3, 579... 

Benzyl carbamates substituted with one or more halogens are much more stable to acidic hydrolysis than are the unsubstituted benzyl carbamates.For example, the 2,4-dichlorobenzyl carbamate is 80 times more stable to acid than is the simple benzyl derivative. Halobenzyl carbamates can also be cleaved by hydrogenolysis with Pd-C. The following halobeni yl carbamates have been found to be useful when increased acid stability is required. 

Important differences are seen when the reactions of the other halogens are compared to bromination. In the case of chlorination, although the same chain mechanism is operative as for bromination, there is a key difference in the greatly diminished selectivity of the chlorination. For example, the pri sec selectivity in 2,3-dimethylbutane for chlorination is 1 3.6 in typical solvents. Because of the greater reactivity of the chlorine atom, abstractions of primary, secondary, and tertiary hydrogens are all exothermic. As a result of this exothermicity, the stability of the product radical has less influence on the activation energy. In terms of Hammond s postulate (Section 4.4.2), the transition state would be expected to be more reactant-like. As an example of the low selectivity, ethylbenzene is chlorinated at both the methyl and the methylene positions, despite the much greater stability of the benzyl radical ... 

Addition of carbon and fluorine can also be initiated by elettraphilic attack on a/luorinated otefin under strongly acidic conditions [250, 251, 252,253 254 255] Best known are fluoroalkylations ot tetrafluoroethylene by tertiary or highly halogenated allylic or benzylic cations in the presence of antimony pentafluoride (equation 53)... 

Polyethylene glycol (molecular weight, 300-6(W) can aid in the displacement of activated halogen by fluorine. Propionyl chloride is converted to propionyl fluoride with potassium fluoride and polyethylene glycol in acetonitrile [63] Treatment of benzyl chloride with a mixture of potassium fluoride and potassium iodide for 5 h in acetonitrile containing polyethylene glycol 200 gives benzyl fluoride in 62% yield [64],... 

Many reactions of fluorinated organics with metal halides result in the replacement of fluorine with halogen A general route to 1,1,1-trichloro- or tribromo-fluoroalkanes involves treating primary fluoroalkyl iodides with aluminum trichloride or aluminum tribromide [74], Benzylic [75, 76] or vinylic [72] fluorine can be exchanged for chlorine when treated with aluminum trichloride... 

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