Palladium-Catalyzed C-H Alkylation

After a stereochemical and mechanistic investigation of palladium-catalyzed tandem intramolecular ort/ro-alkylation/Heck reaction of secondary iodides, this 

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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). 

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.

Scheme 19.10 Palladium-catalyzed C-H alkylation via the Catellani reaction.

Although a stoichiometric palladium complex was often required, palladium-catalyzed C-H alkylation of indole at the C2 position was used in syntheses of complex natural products decades ago. For example, in 1993, the total synthesis of (-l-)-paraherquamide B was reported by Williams and coworkers using a reductive... 

In 2014, Fin, Yao, and coworkers also synthesized rhazinilam by palladium-catalyzed C-H functionalization (Scheme 16.13b) [29]. In their synthesis, pyrrole 75, which is slightly different from Gaunt s intermediate 72, was used. The palladium-catalyzed C-H alkylation of 75 successfully occurred, and they accomplished the synthesis of rhazinilam after several more steps. 

A copper(ii) oxide-catalyzed regioselective synthesis of 1-alkyl- and l-aryl-l//-indazoles from ortho-hzXogcnztcA alkanoylphenones, benzophenones, and arylcarboxylic acids with hydrazines in the presence of potassium carbonate has been developed <20070L525>. A palladium-catalyzed C-H activation/intramolecular amination reaction sequence provided a new route to 3-aryl/alkylindazoles <20070L2931>. 

Different to Yu s work which was directed by the carboxy group [45], in 2012, Guan and coworkers described an alkyl amino-directed palladium-catalyzed C-H carbonylation of Af-alkylanilines to synthesize isatoic anhydrides (Scheme 3.22) [46]. Using 5 mol% Pd(OAc)2, 2.2 equiv. of Cu(OAc)2, and 0.2 equiv. of KI, isatoic... 

The ruthenium-, rhodium-, and palladium-catalyzed C-C bond formations involving C-H activation have been reviewed from the reaction types and mechanistic point of view.135-138 The activation of aromatic carbonyl compounds by transition metal catalyst undergoes ortho-alkylation through the carbometallation of unsaturated partner. This method offers an elegant way to activate C-H bond as a nucleophilic partner. The rhodium catalyst 112 has been used for the alkylation of benzophenone by vinyltrimethylsilane, affording the monoalkylated product 110 in 88% yield (Scheme 34). The formation of the dialkylated product is also observed in some cases. The ruthenium catalyst 113 has shown efficiency for such alkylation reactions, and n-methylacetophenone is transformed to the ortho-disubstituted acetophenone 111 in 97% yield without over-alkylation at the methyl substituent. 

Scheme 19.3 Palladium-catalyzed directed C-H alkylation of acetanilides.

Scheme 19.15 Synthesis of oxindoles by palladium-catalyzed intramolecular C-H alkylation of a-chloroacetanilides.

In addition to directed and intramolecular C-H alkylations, palladium-catalyzed intermolecular C-H alkylations have been reported. In this case, the regioselec-tivity of the C-H bond cleavage is controlled by the natural reactivity of the (hetero)arenes, which corresponds to the longest C-H bond, often correlating with the most acidic C-H bond, in the CMD mechanism [31]. 

Also in 2012, an investigation of the palladium-catalyzed allylic C-H alkylation using Cat. A as catalyst to form compound 22 was performed by Fristrup and coworkers [53] on a reaction that was discovered by White et al. in 2008 (Scheme 8.9) [54]. 

Figure 8.10 Calculated Gibbs free energy profile (kJ mol ) for the palladium-catalyzed allyllc C-H alkylation using DFT/B3LYP-D3.

Palladium-catalyzed synthesis of oxygen-containing heterocycles involving a C-H activation/C-C formation process has been substantially investigated in the past few decades. Palladium-catalyzed arylation, olefination, alkylation. 

Okuyama Y, Nakano H, Takahashi K, Kongo H, Kabuto C (2003) Novel and efficient chiral sulfideoxathiane ligands for palladium-catalyzed asymmetric allylic alkylation. Chem Commun 524-525... 

Fused pyrazole compounds have been prepared from A-alkyl substituted pyrazoles. For example, a palladium-catalyzed/norbornene-mediated sequential coupling reaction involving an aromatic sp2 C-H functionalization as the key step has been described, in which an alkyl-aryl bond and an aryl-heteroaryl bond were formed in one pot <060L2043>. A variety of highly substituted six-membered annulated pyrazoles 59 were synthesized in a one-step process in moderate yields from IV-bromoalkyl pyrazoles 57 and aryl iodides 58. 

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