Direct 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]... 

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

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

Scheme 19.37 Palladium-catalyzed directed C-H alkylation with organotin reagents.

Thereafter, the same group designed chiral monoprotected amino acid ligands for the enantioselective directed C-H alkylation with boronic acids (Scheme 19.40) [61]. Moderate to high enantioselectivities (54-95% ee) were obtained in this desymmetrization reaction performed in the presence of ligand L3. A modest but seminal enantioselectivity (37% ee) was also achieved in one case of C(sp )-H alkylation. 

Wang, Shi, and coworkers [70] reported the cobalt-catalyzed directed C-H alkylation of benzo[h]quinoHne with alkyl Grignard s reagents (Scheme 19.44). The reaction occurred at room temperature but proved less efficient and general than the corresponding C-H arylation. Interestingly, when isopropylmagnesium bromide was employed, a mixture of Hnear and branched products was obtained. The... 

Scheme 19.83 Tandem pyridine-directed C-H alkylation/cycloisomerization.

Formyl pyrrole 86 was arylated with a series of electron-deficient aryl chlorides in the presence of a palladium—Ai-heterocyclic carbene complex. The catalyst complexes were found to he air stable and delivered the pyrrole products in moderate to good yields with loadings as low as 1% (13BJOC303). Jiao and Bach reported the direct C—H alkylation of electron-deficient pyrroles (87) with a palladium catalyst and norbornene yields were very good and the alkyl partner was tolerant of a wide variety of substituents including esters, acetals, olefins, and nitriles (13AG(I)6080). 

Although rare, the direct C-H alkylation of p)fridine is known with both alkene and alkyl halide coupling partners in the... 

Scheme 13.24 Visible-light-mediated direct C-H alkylation of electron-rich heterocycles.

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