Intermolecular amidation of unactivated sp2 and sp2 C-H bonds via palladium-catalyzed cascade C-H activation/nitrene insertion

This communication describes the Pd(OAc)2-catalyzed intermolecular amidation reactions of unactivated sp2 and sp3 C-H bonds using primary amides and potassium persulfate. The substrates containing a pendent oxime or pyridine group were amidated with excellent chemo- and regioselectivities. It is noteworthy that reactive C-X bonds were well-tolerated and a variety of primary amides can be effective nucleophiles for the Pd-catalyzed C-H amidation reactions. For the reaction of unactivated sp3 C-H bonds, beta-amidation of 1 degrees sp3 C-H bonds versus 2 degrees C-H bonds is preferred. The catalytic reaction is initiated by chelation-assisted cyclopalladation involving C-H bond activation. Preliminary mechanistic study suggested that the persulfate oxidation of primary amides should generate reactive nitrene species, which then reacted with the cyclopalladated complex.     

Catalytic allylic alkylation via the cross-dehydrogenative-coupling reaction between allylic sp3 C-H and methylenic sp3 C-H bonds

A catalytic allylic alkylation was developed via the cross-dehydrogenative-coupling reaction of allylic sp3 C-H and methylenic sp3 C-H catalyzed by copper bromide and cobalt chloride in the presence of an oxidizing reagent, t-BuOOH. This methodology provides a direct way to use allylic sp3 C-H bonds for forming C-C bonds.     

Propargylation of 1,3-dicarbonyl compounds with 1,3-diarylpropynes via oxidative cross-coupling between sp3 C-H and sp3 C-H

A highly efficient oxidative-coupling reaction between diarylpropargylic sp(3) C-H and active methylenic sp(3) C-H was achieved with DDQ as oxidant. The reaction afforded a direct method for the propargylation of 1,3-dicarbonyl compounds, thus providing a concise synthesis of the corresponding products.     

CuBr-catalyzed direct indolation of tetrahydroisoquinolines via cross-dehydrogenative coupling between sp3 C-H and sp2 C-H bonds

A novel and efficient C-C bond formation method was developed via the cross-dehydrogenative coupling (CDC) reaction of indoles and tetrahydroisoquinolines catalyzed by copper bromide in the presence of an oxidizing reagent, tert-BuOOH. The CDC reaction provides a simple and efficient catalytic method to construct indolyl tetrahydroisoquinolines via a combination of sp3 C-H bond and sp2 C-H bond followed by C-C bond formation.     

Highly regioselective arylation of sp3 C-H bonds catalyzed by palladium acetate

A new palladium-catalyzed arylation process based on C-H activation has been developed. The utilization of pyridine-containing directing groups allows the beta-arylation of carboxylic acid derivatives and gamma-arylation of amine derivatives. Both primary and secondary sp3 C-H bonds, as well as sp2 C-H bonds, are reactive.     

Highly efficient copper-catalyzed nitro-Mannich type reaction: cross-dehydrogenative-coupling between sp3 C-H bond and sp3 C-H bond

A novel C-C bond formation method was developed via the cross-dehydrogenative-coupling (CDC) reaction catalyzed by using copper bromide in the presence of an oxidizing reagent, tert-BuOOH. The CDC reaction provides a simple and efficient catalytic method to construct beta-nitroamine via the reaction between sp3 C-H and sp3 C-H bonds.     

C-H...N and C-H...S hydrogen bonds--influence of hybridization on their strength

Simple complexes connected through C-H...S and C-H...N interactions are investigated: CH4...NH3, C2H4...NH3, C2H2...NH3, CH4...SH2, C2H4...SH2, and C2H2...SH2. Ab initio and DFT calculations are performed (SCF, MP2, B3LYP) using different basis sets up to the MP2/aug-cc-pVQZ//MP2/aug-cc-pVDZ level of approximation. The Bader theory is applied since MP2/6-311++G(d,p) wave functions are used to find and to characterize bond critical points in terms of electron densities and their Laplacians. The influence of hybridization on the properties of C-H...S and C-H...N systems is also studied showing that the strength of such interactions increases in the following order: C(sp3)-H...Y, C(sp2)-H...Y, C(sp)-H...Y, where Y = S, N--it is in line with the previous findings on C-H...O hydrogen bonds. The results also show that CH4...SH2 and C2H4...SH2 complexes should be rather classified as van der Waals interactions and not as hydrogen bonds. The frequency associated with the C-H stretch of C(sp3)-H...S is blue-shifted.     

Solvent-controlled switch of selectivity between sp2 and sp3 C-H bond activation by platinum(II)

By merely changing the solvent, two different cyclometalated platinum complexes resulted from either sp(2) or sp(3) C-H bond activation can be prepared selectively. For example, the reaction of L1 with K(2)PtCl(4) in MeCN gave exclusively kinetic product 1a, while the reaction in AcOH was thermodynamically controlled and produced predominantly 1b.     

Intermolecular Ritter-type C-H amination of unactivated sp3 carbons

Intermolecular Ritter-type C-H amination of unactivated sp(3) carbons has been developed. This new reaction proceeds under mild conditions using readily available reagents and an inexpensive source of nitrogen (acetonitrile). A broad scope of substrates can be aminated with this method since many functional groups are tolerated. This reaction also allows for the direct, innate C-H amination of a variety of hydrocarbons such as cyclohexane without the need of prefunctionalization or installation of a directing group.     

Direct sp3 C-H bond activation adjacent to nitrogen in heterocycles

Activation of sp(3) C-H bonds adjacent to nitrogen in heterocycles is an attractive transformation that is emerging as a practical method in organic synthesis. This tutorial review aims to summarize the key examples of direct functionalization of nitrogen-containing heterocycles via metal-mediated and metal-catalyzed processes, which is meant to serve as a foundation for future investigations into this rapidly developing area of research. The review covers functionalization of N-heterocycles via alpha-lithiation with alkyllithium/diamine complexes, alpha-amino radical formation, metal-catalyzed direct C-H activation, C-H oxidations and oxidative couplings, and metal-catalyzed carbene insertions.     

Copper-catalyzed oxidative sp3 C-H bond arylation with aryl boronic acids

An efficient method was developed for arylation of sp(3) C-H bonds using copper bromide as catalyst in absence of directing group with arylboronic acids. The oxidative arylation provides easy access to biologically active tetrahydroisoquinoline derivatives and can either use peroxide or molecular oxygen as oxidant.     

CuBr-catalyzed efficient alkynylation of sp3 C-H bonds adjacent to a nitrogen atom

A simple and effective catalytic method to construct propargylamine was developed by using copper bromide and tert-BuOOH via a combination of sp3 C-H bond and sp C-H bond activations followed by C-C bond formation.     

Palladium-catalyzed oxygenation of unactivated sp3 C-H bonds

This communication describes a new palladium-catalyzed method for the oxygenation of unactivated sp3 C-H bonds. A wide variety of alkane substrates containing readily available oxime and/or pyridine directing groups are oxidized with extremely high levels of chemo-, regio-, and in some cases diastereoselectivity. The substrate scope of these reactions is discussed, and the high selectivities are rationalized on the basis of the requirements of putative palladium alkyl intermediates.     

Palladium-catalyzed oxidative sp2 C-H bond acylation with alcohols

An efficient method was developed for the direct acylation of arene sp(2) C-H bonds with alcohols using palladium chloride as a catalyst and peroxide as the oxidant. The alcohols were oxidized to their corresponding aldehydes in situ and efficiently coupled with 2-arylpyridines to give aryl ketones in chlorobenzene.     

Pd(II)-catalyzed cross-coupling of sp3 C-H Bonds with sp2 and sp3 boronic acids using air as the oxidant

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.     

Synthesis of new class of alkyl azarene pyridinium zwitterions via iodine mediated sp3 C-H bond activation

An efficient and conceptually different approach toward C-H bond activation by using iodine mediated sp(3) C-H functionalization for the synthesis of alkyl azaarene pyridinium zwitterions is described. This work has the interesting distinction of being the first synthesis of a new class of alkyl azaarene pyridinium zwitterion via transition-metal-free sp(3) C-H bond activation of an alkyl azaarene.     

Heterocycle synthesis via direct C-H/N-H coupling

A method for five- and six-membered heterocycle formation by palladium-catalyzed C-H/N-H coupling is presented. The method employs a picolinamide directing group, PhI(OAc)(2) oxidant, and toluene solvent at 80-120 °C. Cyclization is effective for sp(2) as well as aliphatic and benzylic sp(3) C-H bonds.     

Catalytic enantioselective alkynylation of prochiral sp3 C-H bonds adjacent to a nitrogen atom

[reaction: see text] The construction of chiral carbon centers via the first catalytic asymmetric alkynylation of prochiral CH2 groups was developed by using a copper-catalyzed double activation of sp3 and sp C-H bonds. Optically active 1-alkynylated tetrahydroisoquinolines were obtained by this method.     

Direct ortho-acetoxylation of anilides via palladium-catalyzed sp(2) C-H bond oxidative activation

Various anilides have been directly ortho-acetoxylated through a Pd(OAc)2-catalyzed C-H bond activation process. The amide group in anilides was found to functionalize as an elegant directing group to convert aromatic sp(2) C-H bonds into C-O bonds in high regioselectivity with acetic acid as the acetate source and K(2)S(2)O(8) as the oxidant.     

C-H bond activation of hydrocarbons by an imidozirconocene complex

Monomeric imidozirconocene complexes of the type Cp2(L)Zr=NCMe3 (Cp = cyclopentadienyl, L = Lewis base) have been shown to activate the carbon-hydrogen bonds of benzene, but not the C-H bonds of saturated hydrocarbons. To our knowledge, this singularly important class of C-H activation reactions has heretofore not been observed in imidometallocene systems. The M=NR bond formed on heating the racemic ethylenebis(tetrahydro)indenyl methyl tert-butyl amide complex, however, cleanly and quantitatively activates a wide range of n-alkane, alkene, and arene C-H bonds. Mechanistic experiments support the proposal of intramolecular elimination of methane followed by a concerted addition of the hydrocarbon C-H bond. Products formed by activation of sp2 C-H bonds are generally more thermodynamically stable than those formed by activation of sp3 C-H bonds, and those resulting from reaction at primary C-H bonds are preferred over secondary sp3 C-H activation products. There is also evidence that thermodynamic selectivity among C-H bonds is sterically rather than electronically controlled.