C—H alkylation

Scheme 20 The diastereoselective direct C—H alkylation of six-membered N-heterocycles...

Complex 9 remains one of the most broadly applicable catalysts for this reaction, catalyzing hydroaminoalkylation with A -arylalkylamines, including controlled monoalkylation of dienes. This reactive catalyst 9 even displays tolerance of oxygen-containing substrates. Most importantly, this remains the only catalytic system capable of the direct C—H alkylation a to N of unprotected heterocyclic amine substrates. Such products are potentially important structural motifs for exploration in medicinal chemistry. In all cases this precatalyst shows regioselective hydroaminoalkylation to generate the branched product, and excellent diastereoselectivity when applicable (Scheme 20). [79]... 

Another excellent example of allylic C—H alkylation has been developed using a Pd (OAc)2-bis-sulfoxide catalyst (Equation 11.8) [19]. Bis-sulfoxide is a crucial and efficient ligand for the transformation. The regioselectivity of the allylation reactions is controlled by steric effects. The synthetic utility of this method is highlighted by the subsequent transformation of its product. 

Despite recent advances in C—H bond functionalization, the enantioselective C—H alkylation of pyridines remains almost unexplored. The only precedent example was reported by Rodewald and Jordan in 1994 using chiral-zircono-cene Cll as the catalyst. The asymmetric C—H bond alkylation of 2-pico-line to 1-hexene was obtained in 19% yield and 58% ee (Scheme 5.71). 

The synthesis of dictyodendrins A and F was realized through a sequential C—H functionahzation strategy inclusive of an initial C3 arylation, a site-selective double C—H alkylation with an aryldiazoacetate derivative and a subsequent Suzuki-Miyaura cross-coupHng with indole-3-boronic acid pinacol ester 107 (2015JAC644). A formal 67r-electrocyc-lization of the resultant tetrasubstituted pyrrole 108 fashioned the required pyrrolo-[2,3-c]carbazole core (109) which was further elaborated to the targets. 

It is proposed that, first, insertion of Sc into the C —H bond occurs, followed by the addition of the 7 C —H alkyl bond with H2 elimination/ ... 

Scheme 11 Synthesis of ( )-solenopsin A via Ru-catalyzed directed C-H alkylation...

In this chapter, the recent progress in transition-metal-catalyzed C-H alkylation (until the end of 2011) will be presented. These reactions have been divided into three categories differing in the nature of the alkylating agent an electrophilic alkyl source (Scheme 19.2a, part 2), an alkyl metal (Scheme 19.2b, part 3), or an alkene (hydroarylation of alkenes. Scheme 19.2c, part 4). Reactions that do not involve the formation of a (hetero)arene-transition metal intermediate during the catalytic cycle have been excluded. Extensions to nonaromatic C(sp )-H bonds, that is, C(sp )-H of alkenes, and C(sp )-H bonds wiU also be reviewed. As for... 

Scheme 19.2 Types of C-H alkylations discussed in this chapter.

Pioneering work on the use of a directing group in palladium-catalyzed C-H alkylation was disclosed by Tremont and coworkers. Acetanilides [7] and aldimines [8] were successfully ortho-metaUated using stoichiometric palladium acetate and then reacted with alkyl or allyl halides. The reaction also proceeded with catalytic amounts of palladium when silver acetate was added to regenerate Pd(OAc)2 (Scheme 19.3). 

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. 

Scheme 19.4 Mechanism of palladium-catalyzed directed C-H alkylation of acetanilides.

Scheme 19.6 Palladium-catalyzed C-H alkylation of arenes with 8-aminoquinoline as directing group.

Scheme 19.8 Picolinamide as auxiliary for the palladium-catalyzed C-H alkylation of benzylamines.

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