Addition multiple, regioselectivity

As far as substrates are concerned, while the usual 1,4-addition and 1,3-substi-tution (Sn2 ) reactions of simple unsaturated substrates have so far predominated, analogous transformations of ambident substrates with extended multiple bond systems (i.e., with two or more reactive positions) have come to attention only recently. Here, systematic investigations have shown that such 1,5-substitutions and even 1,6- and 1,8-addition reactions proceed highly regioselectively and ste-reoselectively, in particular when the substrate contains at least one triple bond besides one or more conjugated double bonds. These unusual reaction types not... 

Cycloadditions to [6,6]-double bonds of Cjq are among the most important reactions in fullerene chemistry. For a second attack to a [6,6]-bond of a C q monoadduct nine different sites are available (Figure 10.1). For bisadducts with different but symmetrical addends nine regioisomeric bisadducts are, in principle, possible. If only one type of symmetrical addends is allowed, eight different regioisomers can be considered, since attack to both e - and e"-positions leads to the same product. Two successive cycloadditions mostly represent the fundamental case and form the basis for the regioselectivity of multiple additions. In a comprehensive study of bisadduct formations with two identical as well as with two different addends, nucleophilic cyclopropanations, Bamford-Stevens reactions with dimethoxybenzo-phenone-tosylhydrazone and nitrene additions have been analyzed in detail (Scheme 10.1) [3, 9, 10]. 

In 1994, Diederich and co-workers reported a very important approach for the regioselective formation of multiple adducts of Cjq by tether-directed remote functionalization [75]. This technique allows for the synthesis offullerene derivatives with addition patterns that are difficult to obtain by thermodynamically or kinetically controlled reactions with free untethered addends. This important subject has been extensively reviewed [26, 76, 77]. 

Disulfide formation using a mixture of chlorosilanes and sulfoxides is a novel oxidation procedure developed independently by Akaji et al. 94-95 and Koide et al. 96 The reagents oxidatively cleave almost all types of S-protecting groups including those which are not oxidatively cleaved by iodine. Therefore, this procedure offers an additional dimension to the strategies of regioselective multiple-disulfide formation (see Section 6.1.4.2). 

In the process of olefin insertion, also known as carbometalation, the 1,2 migratory insertion of the coordinated carbon-carbon multiple bond into the metal-carbon bond results in the formation of a metal-alkyl or metal-alkenyl complex. The reaction, in which the bond order of the inserted C-C bond is decreased by one unit, proceeds stereoselectively ( -addition) and usually also regioselectively (the more bulky metal is preferentially attached to the less substituted carbon atom. The willingness of alkenes and alkynes to undergo carbometalation is usually in correlation with the ease of their coordination to the metal centre. In the process of insertion a vacant coordination site is also produced on the metal, where further reagents might be attached. Of the metals covered in this book palladium is by far the most frequently utilized in such transformations. 

Multiple-component difunctionalization reactions of a,/ -unsaturated carbonyl systems have been achieved by catalytic conjugate addition/aldol sequences. As Scheme 8.13 illustrates, an efficient method reported by Montgomery [46] allows regioselective addition of an aryl iodide to the /i-position of an unsaturated ester under nickel catalysis and subsequent trapping with an aldehyde to give / -hydroxyesters (e.g. 33). Significantly, premature termination of the sequence by the /Miydride elimination process that is usually observed in Pd-catalyzed Heck reactions does not occur here. 

Other tethers have been employed in the search for regioselectivity in multiple additions to fullerenes. Some of these methodologies include the use of bis(o-quinodimethanes) connected by a, oo-dioxamethylene tethers [40], tethered nucleophilic vinylcarbenes [41] or azides [42],... 

The preceding sections describe regioselective electrophilic addition of pyrrole complexes at the 3-position with various electrophiles to give ( -substituted lZ/-pyrrole or 3//-pyrrolium isomers. The latter compounds, in contrast to their noncomplexed counterparts, are only moderately acidic (pKa 6) and therefore resist rearomatization and multiple alkylations. For example, when uncomplexed 2,5-dimethylpyrrole is treated with 1 equiv of methyl acrylate and TBSOTf, a statistical 1 2 1 ratio of starting material, monoalkylated 105 (vide infra), and 3,4-bis-alkylated product is found.12 Treatment of 1-methylpyrrole under the same conditions results in at least four alkylated products along with starting material. In contrast, coordination by osmium results in smooth... 

The photochemical addition of 2H-azirines to the carbonyl group of aldehydes, ketones and esters is completely regiospecific (77H143). Besides the formation of the isomeric oxazolines 18 from 3 and ethyl cyanoformate, there is also formed the imidazole 19 from addition to the C = N in the expected regioselective manner. Thioesters lead to thiazolines 20, while isocyanates and ketenes produce heterocycles 21 (Scheme 4). The photocycloaddition of arylazirines with a variety of multiple bonds proceeds in high yield and provides a convenient route for the synthesis of five-membered heterocyclic rings. Some of the dipolarophiles include azodicarboxylates, acid chlorides, vinylphospho-nium salts and p-quinones. 

Aluminum trichloride catalyzed hydrosilation provides an interesting alternative to the free radical process. The addition of the silane was found to occur regioselectively at trisubstituted alkenes in a frans -fashion. Mechanistically it was concluded that the reaction proceeds via the addition of a silylenium cation to the multiple bond, generating the more stable (more substituted) carbocation, which abstracts a hydride from another molecule of hydrosilane (Scheme 2). ... 

Snider has found dialkyl aluminium halides to be excellent catalysts for this reaction and they can be used to stop the reaction after the first step. This is a real advance in the Prins reaction that otherwise tends to give a mixture of products by multiple addition of the aldehyde and intervention by various nucleophiles. A simple example is the addition of formaldehyde to the terpene limonene 208 catalysed by BF3. A single monoadduct 210 is formed in good yield.34 This must be a Lewis acid catalysed carbonyl ene reaction on the external double bond 209. Notice the excellent chemoselectivity in that the internal alkene is not attacked and the excellent regioselectivity in that hydrogen atoms at four other sites might have taken part in the reaction, but do not. 

Stoichiometric cycloruthenation reactions, as well as the early example of catalytic deuteration of phenol (see above) [38] served for the development of efficient catalytic strategies for C-C bond formations through C-H bond functionalizations. Indeed, ruthenium-catalyzed atom-economical [51] addition reactions of arenes onto C-C multiple bonds, hydroarylations [52-57], were found to be very useful. In an early example, Lewis and Smith disclosed a regioselective alkylation of phenol through in situ formation of its phosphite, and subsequent directed C-H bond functionalization (Scheme 8) [58],... 

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