Cross-coupling by a noncanonical mechanism involving the addition of aryl halide to Cu(II).

Copper complexes are widely used in the synthesis of fine chemicals and materials to catalyze couplings of heteroatom nucleophiles with aryl halides. We show that cross-couplings catalyzed by some of the most active catalysts occur by a mechanism not previously considered. Copper(II) [Cu(II)] complexes of oxalamide ligands catalyze Ullmann coupling to form the C-O bond in aryl ethers by concerted oxidative addition of an aryl halide to Cu(II) to form a high-valent species that is stabilized by radical character on the oxalamide ligand.

A machine-learning tool to predict substrate-adaptive conditions for Pd-catalyzed C-N couplings.

Machine-learning methods have great potential to accelerate the identification of reaction conditions for chemical transformations. A tool that gives substrate-adaptive conditions for palladium (Pd)-catalyzed carbon-nitrogen (C-N) couplings is presented. The design and construction of this tool required the generation of an experimental dataset that explores a diverse network of reactant pairings across a set of reaction conditions.

Streamlined Synthesis of Diaminopyridines by Pd-Catalyzed Ammonia Coupling with Deactivated Amino-Chloropyridines.

An efficient and cost-effective two-step synthesis of diaminopyridines, fundamental building blocks of biologically active compounds, is reported. The advantages over previously reported routes include cost and wider availability of the bromo-chloropyridine starting materials and the straightforward accessibility to an extended array of diaminopyridine regioisomers. The key enabler of this synthetic strategy is the development of an unprecedented palladium-catalyzed coupling reaction of ammonia with chloropyridines deactivated by the presence of an alkylamino substituent.

Highly Efficient Synthesis of a Staphylococcus aureus Targeting Payload to Enable the First Antibody-Antibiotic Conjugate.

A practical synthesis of the complex payload for an anti-Staphylococcus aureus THIOMAB antibody-antibiotic conjugate (TAC) is described. The route takes advantage of a delicate oxidative condensation, achieved using a semi-continuous flow procedure. It allows for the generation of kilogram quantities of a key intermediate to enable a mild nucleophilic aromatic substitution to the tertiary amine free drug.

Asymmetric Synthesis of Akt Kinase Inhibitor Ipatasertib.

A highly efficient asymmetric synthesis of the Akt kinase inhibitor ipatasertib (1) is reported. The bicyclic pyrimidine 2 starting material was prepared via a nitrilase biocatalytic resolution, halogen-metal exchange/anionic cyclization, and a highly diastereoselective biocatalytic ketone reduction as key steps. The route also features a halide activated, Ru-catalyzed asymmetric hydrogenation of a vinylogous carbamic acid to produce α-aryl-β-amino acid 3 in high yield and enantioselectivity.

Sterically Congested 2,6-Disubstituted Anilines from Direct C-N Bond Formation at an Iodine(III) Center.

2,6-Disubstituted anilines are readily prepared from the direct reaction between amides and diaryliodonium salts. As demonstrated for 24 different examples, the reaction is of unusually broad scope with respect to the sterically congested arene and the nitrogen source, occurs without the requirement for any additional promoter, and proceeds through a direct reductive elimination at the iodine(III) center. The efficiency of the coupling procedure is further demonstrated within the short synthesis of a chemerin binding inhibitor.

Cu-catalyzed aerobic oxidative cyclization of guanidylpyridines and derivatives.

A new method for the straightforward synthesis of 2-amino-[1,2,4]triazolo[1,5-a]pyridines and derivatives is presented. The target products are synthesized in high yields from guanidylpyridines and analogues via copper-catalyzed N-N coupling. The present methodology shows a wide scope, tolerating not only different substituents on the pyridine ring but also different heterocylic rings such as pyrazines, pyrimidines, and pyridazines.

Reactivity of a hypervalent iodine trifluoromethylating reagent toward THF: ring opening and formation of trifluoromethyl ethers.

1-Trifluoromethyl-1,2-benziodoxol-3-(1H)-one (1) is able to transfer the electrophilic CF(3) group to the oxygen atom of THF in the presence of a Lewis or Bronsted acid. This results in a new ring-opening reaction of THF yielding trifluoromethyl ethers. Details of this reaction and the insight gained into the mechanism of action of reagent 1 are reported.

Platinum(II) mediated C(sp3)-H activation of tetramethylthiourea.

The C-H activation of the methyl group of tetramethylthiourea by cis-[PtL(2)(NO(3))(2)] (L = phosphine or N-heterocyclic carbene) has been investigated as a function of the ligand L. The presence of an electron-withdrawing group on the tertiary phosphine was found to promote the process. Moreover, when an excess of nitrate anion is present in the reaction mixture, the rate of C-H bond activation is retarded, suggesting the key role of an unsaturated tri-coordinate Pt(II) species as intermediate.

Activation of hydrogen by palladium(0): formation of the mononuclear dihydride complex trans-[Pd(H)2(IPr)(PCy3)].

An even split: In sharp contrast with the general behavior of Pd(0) complexes, [Pd(IPr)(PCy(3))] is able to activate the H-H bond. The resulting trans-[Pd(H)(2)(IPr)(PCy(3))] is the first isolated mononuclear dihydride palladium compound. Its formation is supported by multinuclear NMR spectroscopy, density functional calculations, and X-ray diffraction studies.

A general synthetic route to mixed NHC-phosphane palladium(0) complexes (NHC=N-heterocyclic carbene).

Mixed NHC-phosphane palladium(0) complexes [(NHC)Pd(PR(3))] (NHC: N-heterocyclic carbene) are synthesized directly from commercially available reagents, with the possibility to tune the nature of both the NHC and the phosphane. Reaction of [(NHC)Pd(allyl)Cl] (palladium source) and PR(3), in the presence of a base afforded, in isopropanol, [(NHC)Pd(PR(3))] in good yields. We found that the nature of the solvent played a key role in the efficient reduction of the Pd(II) precursor to Pd(0).

Thermodynamic, kinetic, and computational study of heavier chalcogen (S, Se, and Te) terminal multiple bonds to molybdenum, carbon, and phosphorus.

Enthalpies of chalcogen atom transfer to Mo(N[t-Bu]Ar)3, where Ar = 3,5-C6H3Me2, and to IPr (defined as bis-(2,6-isopropylphenyl)imidazol-2-ylidene) have been measured by solution calorimetry leading to bond energy estimates (kcal/mol) for EMo(N[t-Bu]Ar)3 (E = S, 115; Se, 87; Te, 64) and EIPr (E = S, 102; Se, 77; Te, 53). The enthalpy of S-atom transfer to PMo(N[ t-Bu]Ar) 3 generating SPMo(N[t-Bu]Ar)3 has been measured, yielding a value of only 78 kcal/mol. The kinetics of combination of Mo(N[t-Bu]Ar)3 with SMo(N[t-Bu]Ar)3 yielding (mu-S)[Mo(N[t-Bu]Ar)3]2 have been studied, and yield activation parameters Delta H (double dagger) = 4.