Copper-Catalyzed Dehydrogenative Amidation of Light Alkanes.

The functionalization of C-H bonds in light alkanes, particularly to form C-N bonds, remains a challenge. We report the dehydrogenative coupling of amides with C1-C4 hydrocarbons to form N-alkyl amide products with tBuOOtBu as oxidant, and a copper complex of a phenanthroline-type ligand as catalyst. The reactions occurred in good yields in benzene or supercritical carbon dioxide as solvents. This strategy allowed for the determination of the relative reactivity of these alkane C-H bonds toward this amination process and showed, in contrast to prior work with larger alkanes, that the reactivity correlated with bond dissociation energies.

Nickel-catalysed anti-Markovnikov hydroarylation of unactivated alkenes with unactivated arenes facilitated by non-covalent interactions.

Anti-Markovnikov additions to alkenes have been a longstanding goal of catalysis, and anti-Markovnikov addition of arenes to alkenes would produce alkylarenes that are distinct from those formed by acid-catalysed processes. Existing hydroarylations are either directed or occur with low reactivity and low regioselectivity for the n-alkylarene. Herein, we report the first undirected hydroarylation of unactivated alkenes with unactivated arenes that occurs with high regioselectivity for the anti-Markovnikov product. The reaction occurs with a nickel catalyst ligated by a highly sterically hindered N-heterocyclic carbene. Catalytically relevant arene- and alkene-bound nickel complexes have been characterized, and the rate-limiting step was shown to be reductive elimination to form the C-C bond. Density functional theory calculations, combined with second-generation absolutely localized molecular orbital energy decomposition analysis, suggest that the difference in activity between catalysts containing large and small carbenes results more from stabilizing intramolecular non-covalent interactions in the secondary coordination sphere than from steric hindrance.

Mechanistic Investigations of the Hydrogenolysis of Diaryl Ethers Catalyzed by Nickel Complexes of N-Heterocyclic Carbene Ligands.

Recent interest in the valorization of lignin has led to reactions involving the cleavage of strong aromatic C-O bonds. However, few experimental mechanistic studies of these reactions have been published. We report detailed mechanistic analysis of the hydrogenolysis of diaryl ethers catalyzed by the combination of Ni(COD)2 (COD = 1,5-cyclooctadiene) and an N-heterocyclic carbene (NHC). Experiments on the catalytic reaction indicated that NaOt-Bu was necessary for catalysis, but kinetic analysis showed that the base is not involved in the rate-limiting C-O bond cleavage. The resting state of the catalyst is an NHC-Ni(η6-arene) complex. Substitution of the coordinated solvent with diaryl ether allowed isolation of a diaryl ether-bound Ni complex. Rate-limiting C-O bond cleavage occurs to generate a three-coordinate product of oxidative addition, a metallacyclic version of which has been prepared independently. Stoichiometric studies show that arene and phenol products are released following reaction with H2. NaOt-Bu was found to deprotonate the phenol product and to prevent formation of inactive NiI dimers.

Palladium-catalysed transannular C-H functionalization of alicyclic amines.

Discovering pharmaceutical candidates is a resource-intensive enterprise that frequently requires the parallel synthesis of hundreds or even thousands of molecules. C-H bonds are present in almost all pharmaceutical agents. Consequently, the development of selective, rapid and efficient methods for converting these bonds into new chemical entities has the potential to streamline pharmaceutical development. Saturated nitrogen-containing heterocycles (alicyclic amines) feature prominently in pharmaceuticals, such as treatments for depression (paroxetine, amitifadine), diabetes (gliclazide), leukaemia (alvocidib), schizophrenia (risperidone, belaperidone), malaria (mefloquine) and nicotine addiction (cytisine, varenicline). However, existing methods for the C-H functionalization of saturated nitrogen heterocycles, particularly at sites remote to nitrogen, remain extremely limited. Here we report a transannular approach to selectively manipulate the C-H bonds of alicyclic amines at sites remote to nitrogen. Our reaction uses the boat conformation of the substrates to achieve palladium-catalysed amine-directed conversion of C-H bonds to C-C bonds on various alicyclic amine scaffolds. We demonstrate this approach by synthesizing new derivatives of several bioactive molecules, including varenicline.

2,2,6,6-Tetramethylpiperidine-catalyzed, ortho-selective chlorination of phenols by sulfuryl chloride.

2,2,6,6-Tetramethylpiperidine (TMP)-catalyzed (1-10%) chlorinations of phenols by SO2Cl2 in aromatic solvents are more ortho selective than with primary and less hindered secondary amine catalysts. Ortho-selective chlorination is successful even with electron deficient phenols such as 2-hydroxybenzaldehyde and 2'-hydroxyacetophenone. Notably, ortho selectivity increases with the reaction temperature. On the other hand, tetraalkylammonium chloride-catalyzed chlorinations are moderately para selective.

Effect of ligand modification on the reactivity of phosphinoamide-bridged heterobimetallic Zr/Co complexes.

The effect of modifying the N-aryl substituent (aryl = mesityl vs. m-xylyl) of the phosphinoamide ligands linking Zr and Co in tris(phosphinoamide)-linked heterobimetallic complexes has been investigated. Treatment of the metalloligand ((i)Pr2PNXyl)3ZrCl (2) (Xyl = m-xylyl) with CoI2 affords the iodide-bridged product ICo((i)Pr2PNXyl)2(µ-I)Zr(η(2-i)Pr2PNXyl) (3) rather than the C3-symmetric isomer observed using the N-mesityl derivative, ICo((i)Pr2PNMes)3ZrCl. Upon two-electron reduction of complex 3, ligand rearrangement occurs to generate the three-fold symmetric reduced complex N2Co((i)Pr2PNXyl)3Zr(THF) (4). Comparison of 4 with the previously reported mesityl-substituted complex N2Co((i)Pr2PNMes)3Zr(THF) (1) reveals similar structural features but with a less sterically hindered Zr apical site in complex 4. An obvious electronic difference between these two complexes is also present based on the drastically different infrared N2 stretching frequencies of 1 and 4. These notable differences lend themselves to different reactivity in both stoichiometric and catalytic reactions. Alkyl halide addition to complex 4 results in homo-coupling products resulting from alkyl radicals rather than the alkyl-bridged or intramolecular C-H activation products formed upon addition of RX to 1. This difference in reactivity with alkyl halides renders complex 3 a less effective catalyst for the Kumada cross-coupling of alkyl halides with n-octylMgBr than ICo((i)Pr2PNMes)3ZrCl, as a greater proportion of homocoupling products are formed under catalytic conditions.