The palladium-catalyzed Suzuki-Miyaura reaction has been utilized as one of the most powerful methods for C-C bond formation. However, Suzuki reactions of electron-deficient 2-heterocyclic boronates generally give low conversions and remain challenging. The successful copper(I) facilitated Suzuki coupling of 2-heterocyclic boronates that is broad in scope is reported. Use of this methodology affords greatly enhanced yields of these notoriously difficult couplings. Furthermore, mechanistic investigations suggest a possible role of copper in the catalytic cycle.

Herein we describe the development of a series of pyrazolopyrimidinone phosphodiesterase 2A (PDE2) inhibitors using structure-guided lead identification and design. The series was derived from informed chemotype replacement based on previously identified internal leads. The initially designed compound , while potent on PDE2, displayed unsatisfactory selectivity against the other PDE2 isoforms. Compound was subsequently optimized for improved PDE2 activity and isoform selectivity. Insights into the origins of PDE2 selectivity are described and verified using cocrystallography. An optimized lead, , demonstrated improved performance in both a rodent and a nonhuman primate cognition model.

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Octahedral, six-coordinate Co 2ϩ can exist in two spin states: S ϭ 3/2 and S ϭ 1/2. The difference in energy between high spin (S ϭ 3/2) and low spin (S ϭ 1/2) is dependent on both the ligand mix and coordination stereochemistry. B3LYP calculations on combinations of neutral imidazole, NH 3 , and H 2 O ligands show that low-spin isomers are stabilized by axial H 2 O ligands and in structures that also include trans pairs of equatorial NH 3 and protonated imidazole ligands, spin crossover structures are predicted from spin state energy differences. Occupied Co d orbitals from the DFT calculations provide a means of estimating effective ligand strength for homoleptic and mixed ligand combinations. These calculations suggest that in a labile biological system, a spin crossover environment can be created.

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Pyridine derivatives R 0380Copper-Facilitated Suzuki Reactions: Application to 2-Heterocyclic Boronates. -These difficult Suzuki couplings are achieved in the presence of a stoichiometric amount of CuCl. -(DENG*, J. Z.; PAONE, D. V.; GINNETTI, A. T.; KURIHARA, H.; DREHER, S. D.; WEISSMAN, S. A.; STAUFFER, S. R.; BURGEY, C. S.; Org. Lett. 11 (2009) 2, 345-347; Dep. Med. Chem., Merck Res. Lab., Rahway, NJ 07065, USA; Eng.) -Nuesgen 24-138

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