Bicyclic primary alkyl

The first total synthesis of the clerodane alkaloid solidago alcohol was achieved in the laboratory of H.-S. Liu, using a highly diastereoselective DIels-Alder cycloaddition as the key step. The installation of the 3-furyl side chain required the conversion of the bicyclic primary alkyl bromide to the corresponding aldehyde. This was accomplished by the modified Kornblum oxidation, which employed silver tetrafluoroborate to activate the substrate. 

The formation of bicyclic imines (263,264) from piperidine enamines and y-bromopropyl amines may appear at first sight to be a simple extension of the reactions of enamines with alkyl halides. However, evidence has been found that the products are formed by an initial enamine exchange, followed by an intramolecular enamine alkylation. Thus y-bromodiethylamino-propane does not react with piperidinocyclohexene under conditions suitable for the corresponding primary amine. Furthermore, the enamine of cyclopentanone, but not that of cyclohexanone, requires a secondary rather than primary y-bromopropylamine, presumably because of the less favorable imine to enamine conversion in this instance. 

Scheme 10.17 illustrates allylation by reaction of radical intermediates with allyl stannanes. The first entry uses a carbohydrate-derived xanthate as the radical source. The addition in this case is highly stereoselective because the shape of the bicyclic ring system provides a steric bias. In Entry 2, a primary phenylthiocar-bonate ester is used as the radical source. In Entry 3, the allyl group is introduced at a rather congested carbon. The reaction is completely stereoselective, presumably because of steric features of the tricyclic system. In Entry 4, a primary selenide serves as the radical source. Entry 5 involves a tandem alkylation-allylation with triethylboron generating the ethyl radical that initiates the reaction. This reaction was done in the presence of a Lewis acid, but lanthanide salts also give good results. 

Davis et al. [88] described the asymmetric synthesis of a-substituted primary sulfonamides involving the diastereoselective a-alkylation of N-sulfonylcamphor-imine dianions, while Huart and Ghosez reported an enantioselective synthesis of bicyclic cyclopentenones via a stereoselective 1,4-addition of metallated enan-tiopure sulfonamides to cyclic enones [89]. 

Chemoselective E2 eliminations can be carried out with sterically hindered, sufficiently strong bases. Their bulkiness causes them to react with an H atom at the periphery of the molecule rather than at a C atom deep within the molecule. These bases are therefore called nonnucleo-philic bases. The weaker nonnucleophilic bases include the bicyclic amidines DBN (diazabi-cyclononene) and DBU (diazabicycloundecene). These can be used to carry out chemoselective E2 eliminations even starting from primary and secondary alkyl halides and sulfonates (Figure 4.17). 

For efficiency and reasons of economy THF is recommended. Representative dehalogenations in THF are shown in Table 1. Most alkyl halides are reduced at 25 C to alkanes, except for bicyclic halides, such as eA o-2-bromonorbomane. In most cases, the reaction exhibits the typical characteristics of an 5n2 substitution reaction in the reactivity order I > Br > Cl primary > secondary > tertiary. In all cases, no al-kene, or only traces of it, is formed as a side product as a result of elimination. This method provides a convenient synthetic procedure for hydrodehalogenation of alkyl halides. 

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