Bridgehead halides

Addition of RJCuLi to bridgehead enones.1 Ordinarily organocuprates do not react with a bridgehead halide. However, they can undergo conjugate addition to bridgehead enones generated in situ from p-bromo ketones with potassium t-butoxide or lithium 2,6-di-r-butyl-4-methylphenoxide (6,95). 

In view of continuous efforts to develop an alternative procedure for the preparation of bridgehead halides from the corresponding carboxylic acids using... 

Nucleophilic substitution, aliphatic, 31, 45, 77-100 Ag catalysis, 97 allyl halides, 85 ambident nucleophiles, 97 benzyl halides, 84, 91 bridgehead halides, 86 bromomethane, 78 2-bromopropanoate, 94 1-bromotriptycene, 87 carbanions in, 100,288... 

Substitutions by the SRn 1 mechanism (substitution, radical-nucleophilic, unimolecular) are a well-studied group of reactions which involve SET steps and radical anion intermediates (see Scheme 10.4). They have been elucidated for a range of precursors which include aryl, vinyl and bridgehead halides (i.e. halides which cannot undergo SN1 or SN2 mechanisms), and substituted nitro compounds. Studies of aryl halide reactions are discussed in Chapter 2. The methods used to determine the mechanisms of these reactions include inhibition and trapping studies, ESR spectroscopy, variation of the functional group and nucleophile reactivity coupled with product analysis, and the effect of solvent. We exemplify SRN1 mechanistic studies with the reactions of o -substituted nitroalkanes (Scheme 10.29) [23,24]. 

Halides that do not undergo SN2 reactions readily (tertiary, cyclopropyl and bridgehead halides) react by silver-assisted substitution in the presence of silver salts89. Tertiary halides have also been reduced using the in situ generation of cyanoborohydride reagents90. Since primary and secondary halides are apparently unaffected by this reagent, a selective reaction has been developed. 

The nitro group does not necessarily have to be in the o- or -position of the benzene ring, nor is the presence of a nitro group a prerequisite for nucleophilic photosubstitution via the S l mechanism to occur. The meta-nitro analogue 35 with a tert-butyl group at Ca displays S l behaviour (with a series of nucleophiles)197 and so do the bridgehead halide 9-bromotriptycene (with phosphide and arsenide ions)32, compound 36 (with nitronate and azide ions)1, compound 37, X = Cl (with nitronate ions)199 and compound 38 (with azide ion)200. For compound 37, X = Br, SN2 substitution is competitive. 

Photostimulated SRN1 reactions of bridgehead halides [119, 120] and of tertiary chlorides [122] has been examined and considered as a possible route to nucleophilic substitution of these normally unreactive substrates. In the case of the reaction of 1-iodoadamantane with ketone enolates, the photosubstitution product yield was improved in the presence of 18-crown-6 [103], This is probably related to the ion pairing effect already discussed in a preceding section. 

Bridgehead halides can also be reduced by LiAIH. I hus l-bromoadamantane is reduced to adamantane in 80 % yield when treated with Li AIH4 in boiling ether for 18 hr. Even 1-bromotriptycene is reduced to the parent hydrocarbon when treated with LiAIH4 in DME for 48 hr. 

Frequently, bond cleavage is used for R-Hal —> R-H dehalogenations [74], and the formation of carbanions [75]. More seldom encountered are reactions of n acceptors that have the a bond spatially well separated and that depend on long-range ET. Such a situation occurs in phenyl-substituted alkyl chlorides [76], and bridgehead halides [77] with various redox relay functions (e.g. a nitroaryl group) [78]. 

Magat first reported the use of r-alkyl halides as Ritter reaction substrates but, in general, these were less satisfactory than the use of the corresponding alcohol or alkene analogs. This process has since come into its own for polycyclic systems, where simple methods of generating bridgehead halides are often available. An early example is Stetter s conversion of 1-bromoadamantane to the acetamide (30), there-... 

Kraus, G. A., Shi, J. Reactions of bridgehead halides. A synthesis of modhephene, isomodhephene, and epi-modhephene. J. Org. Chem. 

These reactions can occur with bridgehead halides which are unreactive by the Sn2 mechanism, for example ... 

Nevertheless, a majority of quasi-Favorskii rearrangements are performed on bridgehead halides that contain ketones in an appropriate location. The synthesis of these systems can be more challenging, but a number of strategies have been devised. 

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