Intermolecular reactions reductive alkylation

A different strategy for the formation of the cyclic core of the BFC is based on peptide bond formations O Fig. 45.10). The macrocycle is formed by an intermolecular reaction of an activated disuccinimido ester with a diamine under high-dilution conditions with a yield of >40%. Reduction of the carbonyl groups and alkylation lead to a BFC, which possesses an attachment function for biomolecules on the carbon backbone of the macrocycKc core (McMurry et al. 1992). 

More recently, Yu and coworkers [9] described the paUadium(II)-catalyzed ortho alkylation of simple benzoic acids with either 1,2-dichloroethane or dibro-momethane (Scheme 19.5). The use of the less activated 1-chloropentane was also feasible, but furnished only a 26% yield. This reaction was shown to proceed through initial intermolecular C-H alkylation followed by intramolecular Sj 2-cyclization to give the corresponding benzolactone. As mentioned, the C-H alkylation step was proposed to occur through oxidative addition-reductive elimination or o-bond metathesis. 

Pearson and coworkers also developed intermolecular reactions of azides with carboca-tions. Thus, benzylic or tertiary alcohols, when treated with alkyl azides in the presence of SnCLt or TfOH followed by NaBH4-mediated reduction, provided tertiary or secondary amines. Both cyclic and acyclic alcohols were compatible with these reactions, though mixtures of constitutionally isomeric products often resulted (Scheme 7.23). 

The great majority of photoredox reachons rely on reductive electron-transfer process to an alkyl halide (usually a bromide) generating an electron-deficient alkyl radical. The so-formed electrophilic radicals can be trapped by electron-rich olefins by intra- or intermolecular reaction [25]. 

The tandem intermolecular-[4 + 2]/intermolecular-[3 + 2] cycloadditions create bicyclic nitroso acetals with up to six stereogenic centers in a predictable fashion (Scheme 16.53). Because both cycloadditions are usually conceited and the geometry of the components is preserved, the relationship between those substituents in the nitroso acetal will also be preserved. For example, in Scheme 16.53 the substituents A and B, as well as E and F in nitroso acetal 237 will take up a cis relationship to each other. However, the relationships B/C, C/D, and D/E are established by the topicity of the cycloaddition events as described below. Upon hydrogenol-ysis, those stereocenters in product 239 are also preserved unless further reactions follow, the most important of which is the loss of the C(6) stereogenic center during reductive alkylation when substituent F is an alkoxy group. 

Both the intramolecular and the intermolecular secondary metathesis reactions affect the polymerisation kinetics by decreasing the rate of polymerisation, because a fraction of the active sites that should be available as propagation species are involved in these non-productive metathesis reactions. The kinetics of polymerisation in the presence of metal alkyl-activated and related catalysts shows in some cases a tendency towards retardation, again due to gradual catalyst deactivation [123]. Moreover, several other specific reactions can influence the polymerisation. Among them, the addition of carbene species to an olefinic double bond, resulting in the formation of cyclopropane derivatives [108], and metallacycle decomposition via reductive elimination of cyclopropane [109] deserve attention. 

The ability of Sml2 to reduce alkyl halides has been exploited in a number of carbon carbon bond-forming reactions. Radicals generated from the reduction of alkyl halides can be trapped by alkenes in cyclisation reactions to form carbocyclic and heterocyclic rings (see Chapter 5, Section 5.3), and the alkyl-samarium intermediates can be used in intermolecular and intramolecular Barbier and Grignard reactions (see Chapter 5, Section 5.4). The reduction of ot-halocarbonyl compounds with Sml2 gives rise to Sm(III) enolates that can be exploited in Reformatsky reactions (Chapter 5, Section 5.5) and are discussed in Section 4.5. 

Molander has also studied the Sml2-mediated double Barbier additions of alkyl dihalides to ketoesters.22,23 These impressive anionic-anionic, inter-molecular-intramolecular sequences require the use of Nil2 as an additive and irradiation with visible light and allow access to a range of bicyclic and tricyclic systems. The reactions proceed by reduction of the more reactive alkyl halide, intermolecular Barbier addition to the ketone, lactonisation and a second Barbier addition to the lactone carbonyl (Scheme 6.18).22... 

Hydrido alkyl species L M(H)(R) are particularly prone to elimination of R—H this thermodynamically favored reaction is the reverse of C—H activation (see Section 21-4) and explains why for a long time intermolecular C—H activation remained elusive. For example, the protolysis of (TMEDA)PtMe2 by HC1 does not lead to the direct electrophilic attack of H+ on the Pt—Me bond but gives thermally unstable hydrido alkyl (TMEDA)Pt(H)ClMe2 which undergoes reductive elimination via a coordinatively unsaturated 5-coordinate intermediate 97... 

Following the pioneer work of Kharasch [60], methods involving radical transfer of halides have been developed. The atom transfer method has emerged in the 1980s as one of the best method for conducting intra- and intermolecular radical additions to olefins [61]. This approach is particularly appealing from an atom economy point of view since all atoms remains in the final product. The non-reductive nature of these reactions is also particularly important for the preparation of functionalized molecules. Halides transfers and more particularly iodine atom transfers have found nice applications for cyclizations, annula-tions and cascade reactions [62]. These reactions are based on exothermic radical steps, such as the addition of an alkyl radical to an olefin, followed by an... 

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