Unactivated sp3 C-H Bonds

O/t/20-arylation of benzoic acids is often preferable to ortho-arylation of benzamides if conversion of the amide moiety to other functional groups is desired. However, only a few reports have dealt with the orf/io-functionalization of free benzoic acids due to challenges that involve such transformations. The reactions can be complicated by decarboxylation of the product and the starting material. Despite those difficulties, several methods for direct o/t/io-arylation of benzoic acids have been developed. Yu has shown that arylboronates are effective in arylation of benzoic acids under palladium catalysis [59], The reactions require the presence of palladium acetate catalyst, silver carbonate oxidant, and benzoquinone. Even more interestingly, the procedure is applicable to the arylation of unactivated sp3 C-H bonds in tertiary carboxylic acids such as pivalic acid (Scheme 13) if aryl iodide coupling partner is used. Aryl trifluoroborates can also be used [60],... 

Scheme 21 Auxiliary-assisted arylation of unactivated sp3 C-H bonds...

Copper Catalysts Copper is an excellent catalyst for nitrogen transfer reactions via copper-nitrene intermediates. Benzylic hydrocarbons are selectively converted to the corresponding sulfonamides [40]. The intermolecular amidation of saturated C—H bonds of cyclic ethers has been reported using TsNH2-PhI(OAc)2 or PhI=NTs as the nitrene source [41]. The copper-catalyzed amidation of unactivated sp3 C—H bonds adjacent to a nitrogen atom has also been achieved using tert-butyl hydroperoxide or... 

Significantly, unactivated sp3 C—H bond oxidation has been achieved using oxime or pyridine as a directing group and PhI(OAc)2 as a stoichiometric oxidant in the presence of a palladium catalyst (Equation 11.28) [66], y-C- H bonds are selectively oxygenated. The selectivity is dramatically influenced by the steric and electronic properties of the alkane substrates. 

Because of the creative minds contributing to the field, the tools of C-H bond transformation available to synthetic chemists are actively expanding [1], Among these, coordination-directed C-H bond-activation has long preserved its appeal, because it enables selective functionalization of a particular C-H bond in the presence of other functional groups. This can be achieved by using a heteroatom (FG = functional group shown in Scheme 1) in the substrate structure to direct the metal complex to the proximity of the specific C-H bond. Even unactivated sp3-centered C-H bonds tend to react in a cyclometalation step with palladium, platinum [2], and ruthenium catalysts [3]. 

Scheme 10.4 Carbonylation of unactivated C(sp3 -H bonds (partially reproduced from Ref [43]).

Hasegawa N, Shibata K, Charra V, Inoue S, Fukumoto Y, Chatani N (2013) Ruthenium-catalyzed cyclocarbonylation of aliphatic amides through the regioselective activatimi of unactivated C(sp3)-H bonds. Tetrahedron 69(22) 4466-4472... 

Wei Y, Tang H, Cong X, Rao B, Wu C, Zeng X (2014) Pd(II)-calalyzed intermolecular arylation of unactivated C(sp3)-H bonds with aryl bromides enabled by 8-aminoquinoline auxiliary. Org Lett 16(8) 2248—2251... 

He G, Chen G (2011) A practical strategy for the structural diversificatirai of aliphatic scaffolds through the palladium-catalyzed picolinamide-diiected remote functitmalization of unactivated C(sp3)-H bonds. Angew Chem Int Ed 5(X22) 5192-5196... 

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