Alkylation palladium-mediated

Palladium-mediated catalysis has only been exploited relatively recently in the synthesis of substituted PPV derivatives. The use of aryl dibromides as monomers is particularly useful as it allows the synthesis of PPVs substituted with alkyl rather than alkoxy sidechains. The Suzuki [53, 54], Heck [55], and Stille [56] reactions have been used in the synthesis of new PPV derivatives, but attaining high molecular weight PPV derivatives by these methodologies has proved problematic. A phenyl-subslilutcd PPV material PPPV 31 was synthesized by a Suzuki coupling (Scheme 1-10) of dibromoethene and fo/.v-boronic acid 30. Its absorption (2ni ix=385 nm) and emission (2max=475 nm) maxima were strongly... 

Several examples have been reported of the use of palladium-mediated oxidation reactions of alcohols and alkyl halides. Palladium(II) acetate in the presence of iodobenzene converts primary and secondary alcohols into carbonyl compounds under solid-liquid two-phase conditions [20], However, other than there being no further oxidation to carboxylic acids, the procedure has little to commend it over other methods. It is relatively slow with reaction times in the order of 2 days needed to achieve yields of 55-100%. 

Support-bound stannanes have been prepared from phenyllithium bound to macro-porous polystyrene and chlorostannanes [14,41], by treatment of support-bound alkyl chlorides with lithiated stannanes [21,41], and by radical or palladium-mediated addition of stannanes to alkenes and alkynes (Figure 4.7 [42-47]). The chloride of poly-styrene-bound chlorostannanes can be displaced by treatment with arylzinc reagents, thereby yielding resin-bound arylstannanes [46]. Polystyrene-bound stannanes have also been prepared by copolymerization of 4-[2-(dibutylchlorostannyl)ethyl]styrene with styrene and divinylstyrene [48],... 

Polystyrene-bound trialkylboranes, which can be prepared by hydroboration of support-bound alkenes with 9-BBN, undergo palladium-mediated coupling with alkyl, vinyl, and aryl iodides (Suzuki coupling Entries 1 and 2, Table 5.3 for vinylations, see Section 5.2.4). Because boranes are compatible with many functional groups and do not react with water, these coupling reactions could become a powerful tool for solid-phase synthesis. To date, however, few examples have been reported. 

Linkers that enable the preparation of y-lactones by cleavage of hydroxy esters from insoluble supports are discussed in Section 3.5.2. Resin-bound y-lactones have been prepared by Baeyer-Villiger oxidation of cyclobutanones [39], by intramolecular addition of alkyl radicals to oximes [48], by electrophilic addition of resin-bound sele-nenyl cyanide or bromide to 3,y-unsaturated acids (Figure 9.2 [100]), and by palladium-mediated coupling of resin-bound aryl iodides with allenyl carboxylic acids (Entry 10, Table 5.7 [101]). 

To expand the diversity of their libraries Brill et al.16 also modified various heterocycles by alkylation, acylation, or metal-mediated coupling reaction prior to resin capture. A remaining chloro substituent was still available for nucleophilic displacement or a palladium-mediated coupling reaction with anilines, phenols, and boronic acids on solid phase [see Fig. 10 for the preparation of purine derivative (62)]. 

Following Ellman s pioneering work on benzodiazepines,2 another study from the same laboratory illustrated the vast potential of combining a variety of chemical reactions on drug-like heterocycles. In this case a preformed heterocycle was grafted as a whole onto the solid phase to be subsequently derivatized via a three-component palladium-mediated coupling reaction followed by a reductive alkylation or an acylation (Fig. 12).34... 

Scheme8.6. Alkyl halides with p hydrogen in palladium-mediated cross-couplings [76, 77].

Clinet, J. C. Balavoine, G. Palladium-mediated ortho-alkylation of 2-aryloxazolines. J. Organomet. Chem. 1991, 405, C29-C31. 

N-Arylation of various azoles (or their anions) was readily accomplished with p-tolyllead triacetate in the presence of copper(II)acetate [95JOC5678] however, die applicability of this procedure to other aryllead triacetates was not discussed. Solvent-dependent palladium-mediated allylations [95JHC1325] and Mitsunobu-based asymmetric alkylations [95JOC2008] of imidazoles and benzimidazoles have also been reported. 

Oxidative coupling was used to form alkyl- and alkoxy-substituted phenanthrenedione products lOOa-d (Table 22) [73]. These compounds can be obtained by other methods, albeit in much lower yields. In this instance, oxidative coupling proceeds even with carbonyl-substituted arenes, and VOF3 gives much better results than thallium- or palladium-mediated coupling procedures. 

An intramolecnlar palladium-mediated allylic alkylation via a ketone enolate of piperidinone 54 was reported by Williams and coworkers for the synthesis of R)-l-hydroxyquinine 57 (eqnations 17 and 18) °. The key step involves a palladium-mediated Sjv2 -type cyclization reaction of enol ether 55 in the presence of BnsSnF, giving rise to a quinuclidine ketone, which was immediately rednced to 56 to avoid equilibration and /3-elimination. Interestingly, none of the undesired C3-vinyl stereoisomer was observed. 

Ellman utilized the Suzuki coupling twice between a support-bound vinyl bromide and an alkyl 9-BBN derivative in a solid-phase synthesis of E- and F-series prostaglandins. The Suzuki reaction was performed in situ, with the hydroboration of a terminal olefin being followed by the palladium-mediated step. This sequence is attractive in library synthesis because of the wide range of suitable commercially available alkenes. The inspiration behind this chemistry was the solution-phase work of Johnson and Braun, where the couplings of 35 with 2-iodo-4-(silyloxy)cyclopent-2-enone 36 went well at room temperature with PdCljCdppO-AsPhj as catalyst (Scheme 41). The modular chemistry demonstrated in this paper was clearly amenable to adaptation to a solid-phase strategy. 

The palladium-mediated substitution of allylic substrates proceeds in two independent steps. For stabilized carbanions both oxidative addition and the nucleophilic displacement occur with inversion of configuration. Thus, overall retention results, in contrast to the corresponding reactions of nonstabilized carbanions as nucleophiles (see Section D.l. 5.6.3.). The steric course of the reaction is proved by the absence of racemization in Lhe conversion of chiral substrates into chiral alkylated products. Furthermore, chiral n-allylpalladium complexes formed with inversion from stoichiometric reactions of palladium(O) with allyl substrates have been isolated. Coupling of these stereodefined complexes with soft carbanions yields the chiral alkylated products, again with inversion of configuration. 

Table 3. Influence of Leaving Group on the Palladium-Mediated Alkylation of Cyclic Allylic Substrates with Soft C-Nucleophiles...

Sulfones are also useful as allylic leaving groups in palladium-mediated alkylations. In particular cyclic 2-sulfonyl-l, 3-dienes, which are readily available from a one-pot sulfonylmercura-tion/elimination of 1,3-dienes, are versatile starting materials107. The palladium-catalyzed substitution of allyl sulfones occurs with net retention of configuration and features attack on the least substituted 7i-allyl terminus108. 

If the substrate lacks a hydrogen suitable for p elimination and there is another alkene present in the molecule, the a-alkyl palladium intermediate can follow a Heck pathway to form a bicyclic structure in a tandem reaction sequence. Once again, the final step is a palladium-hydride-mediated isomerization to give the endocyclic alkene. 

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