This critical review discusses historical and contemporary research in the field of transition metal-catalyzed carbon-hydrogen (C-H) bond activation through the lens of stereoselectivity. Research concerning both diastereoselectivity and enantioselectivity in C-H activation processes is examined, and the application of concepts in this area for the development of novel carbon-carbon and carbon-heteroatom bond-forming reactions is described. Throughout this review, an emphasis is placed on reactions that are (or may soon become) relevant in the realm of organic synthesis (221 references).

The use of preformed sodium carboxylates as substrates led to the first observation of facile Pd-insertions into sp3 β-C−H bonds in simple aliphatic acids. Consequently, Pd-catalyzed methylation and arylation of o-C−H bonds in benzoic acids and β-C−H bonds in aliphatic acids using either a phenylboronate, methylboronic acid, or ArI have been achieved via a C−H activation/C−C coupling sequence.

O-Methyl hydroxamic acids, readily available from carboxylic acids, are found to be extremely reactive for beta-C-H activation by Pd(OAc)2. This reactivity is exploited to develop the first example of cross-coupling sp3 C-H bonds with sp3 boronic acids. Air was shown to be a suitable stoichiometric oxidant for the catalytic oxidative coupling reaction. A biologically active natural product is readily converted to its novel analogues through this coupling reaction.

The catalytic activation of C(sp 3 )ÀH and C(sp 2 )ÀH bonds in readily available, inexpensive starting materials would provide a valuable array of new transformations for organic chemistry research and the fine chemical industry.[1] Activation of C(sp 2 )ÀH bonds in benzene and ortho-substituted arenes has been successfully exploited in the development of catalytic CÀC bond-forming reactions by coupling to olefins. [2,3] The selective activation of C(sp 3 )ÀH bonds under mild conditions could be an attractive strategy for the development of catalytic reactions with wide applicability. Despite extensive efforts that have focused mainly on carbene and nitrene insertions, metathesis, Shilov chemistry, and biomimetic approaches, the catalytic and asymmetric functionalization of C(sp 3 )ÀH bonds remains a significant challenge.[4]We report herein an auxiliary approach for the chemoselective and asymmetric room-temperature iodination of

Unactivated CH3 groups in 2‐oxazolines are oxidized by inexpensive oxidants, such as tert‐butyl peroxyacetate and lauroyl peroxide, in the presence of a catalytic amount of Pd(OAc)2. Carboxylic anhydrides are essential for both the oxidation of the PdC bonds and regeneration of Pd(OAc)2. The use of [D6]Ac2O as the solvent shows that the acetyl group incorporated into the product is from acetic anhydride rather than the oxidant (see scheme).

A Pd(II)-catalyzed reaction protocol for the direct carboxylation of benzoic and phenylacetic acid derivatives to form dicarboxylic acids has been developed. The reaction conditions are also applicable for the carboxylation of vinyl C-H bonds. The first C-H insertion Pd-aryl complex from carboxylic acids has been characterized by X-ray crystallography.

Although the syntheses of novel and diverse peptides rely mainly on traditional coupling using unnatural amino acids, postsynthetic modification of peptides could provide a complementary method for the preparation of nonproteinogenic peptides. Site selectivity of postsynthetic modification of peptides is usually achieved by targeting reactive moieties, such as the thiol group of cysteine or the C-2 position of tryptophan. Herein, we report the development of site-selective functionalizations of inert C(sp3)–H bonds of N-terminal amino acids in di-, tri-, and tetrapeptides without installing a directing group. The native amino acid moiety within the peptide is used as a ligand to accelerate the C–H activation reaction. In the long run, this newly uncovered reactivity could provide guidance for developing site-selective C(sp3)–H activation toward postsynthetic modification of a broader range of peptides.

A series of Cu(I)-amido complexes both lacking ancillary ligands and containing 1,10-phenanthroline (phen) as ligand have been prepared. These complexes react with iodoarenes to form arylamine products, and these data are consistent with the intermediacy of such complexes in catalytic Ullmann amination reactions. The stoichiometric reactions of the Cu(I)-amido complexes with iodoarenes are autocatalytic, with the free CuI generated during the reaction serving as the catalyst. Such autocatalytic behavior was not observed for reactions of iodoarenes with Cu(I)-amidates, -imidates and -phenoxides. The selectivity of these complexes for two sterically distinct aryl halides under various conditions imply that the autocatalytic reaction proceeds by forming highly-reactive [CuNPh 2 ] n lacking phen. Reactions with radical probes imply that the reactions of phen-ligated Cu(I)-amido complexes with iodoarenes occur without the intermediacy of aryl radicals. DFT calculations of the oxidative addition of iodoarenes to Cu(I) species are consistent with faster reactions of iodoarenes with CuNPh 2 species lacking phen in DMSO than with phenligated LCuNPh 2 . The free energy barrier computed for reaction of PhI with (DMSO)CuNPh 2 was 21.8 kcal/mol, while the free energy barrier computed for reaction of PhI with (phen)CuNPh 2 was 33.4 kcal/mol.A century has passed since the discovery of Ullmann reactions in which arylamines couple with aryl halides mediated by copper.1 The synthetic scope of this process remained limited for many decades and often required stoichiometric amounts of copper and high reaction temperatures (typically 200 °C) to obtain satisfactory yields. More recently, copper catalysts containing ancillary ligands have been used, and these systems react with broader scope and at lower temperatures. 2 In 1999, Goodbrand and Hu reported the coupling of arylamines with aryl iodides catalyzed by a combination of 1,10-phenanthroline (phen) and CuCl under jhartwig@illinois.edu. Supporting Information Available: Experimental procedures, computational details and characterization of complexes. This material is available free of charge via the internet at http://pubs.acs.org. Our synthesis of Cu(I)-amido complexes is outlined in Scheme 1. Phen-ligated complex 1, and cuprates 2-4 in which phen and a crown ether ligate to K + or Li + , were prepared by the reaction of CuOtBu with HNPh 2 or a mixture of HNPh 2 and either LiNPh 2 or KNPh 2 in the presence of phen or 18-crown-6 in THF. Cuprates 2 and 3 were also prepared from phen, LiNPh 2 or KNPh 2 , and double salt 1 in THF. Finally, ligandless cuprate 5 was prepared from HNPh 2 , KNPh 2 and CuOtBu in the absence of any dative ligand. These complexes were characterized by elemental analysis and NMR spectroscopy. Solid state structures of complexes 1 and 3 were determined by single crystal X-ray diffraction. NIH Public AccessThe solid state structure of complex 1 (Figure 1) is an ion pair consisting of a tetrahedral, cationic copper ligated by phen and a linear, anionic...