Chunpu Li

An expedient Pd/DBU mediated cyanation of aryl/heteroaryl bromides with K4[Fe(CN)6]

A practical Pd(PPh(3))(4)/DBU catalytic system for the synthesis of pharmaceutically relevant aminopyridine nitrile intermediates, as well as a variety of other aryl nitriles using non-toxic K(4)[Fe(CN)(6)] has been developed. The key features of our new protocol for cyanation lie in that the reaction can be carried out with readily available Pd(PPh(3))(4) under mild and green conditions, even without the assistance of other ligands.

Discovery of novel 2-aminopyridine-3-carboxamides as c-Met kinase inhibitors.

A series of 2-aminopyridine-3-carboxamide derivatives against c-Met were designed and synthesized by employing bioisosteric replacement of heterocyclic moieties with the amide bond. The structure-activity relationship (SAR) at various positions of the scaffold was explored. In this study, a promising compound (S)-24o with a c-Met IC(50) of 0.022 μM was identified. The compound exhibited dose-dependent inhibition of the phosphorylation of c-Met as well as downstream signaling in EBC-1 cells. Furthermore, the interactive binding model of (S)-24o with c-Met was elucidated by virtue of a molecular modeling study.

Cu(II)-catalyzed C6-selective C–H thiolation of 2-pyridones using air as the oxidant

The Cu(II)-catalyzed and chelate-directed C6-selective C–H thiolation of 2-pyridones with disulfides was developed to provide aryl and alkyl thioethers. This transformation uses a catalytic amount of Cu(OAc)2 and molecular oxygen in air as an oxidant, no cocatalysts or metallic oxidants are required. The reaction accommodated both electronic and steric factors at the C3–C5 positions of 2-pyridones, which is efficient for the C6 thiolation of a broad range of 2-pyridones with up to 93% yield.

Synthesis and biological evaluation of 2-amino-5-aryl-3-benzylthiopyridine scaffold based potent c-Met inhibitors.

A series of 2-amino-N-benzylpyridine-3-carboxnamides, 2-amino-N-benzylpyridine-3-sulfonamides and 2-amino-3-benzylthiopyridines against c-Met were designed by means of bioisosteric replacement and docking analysis. Optimization of the 2-amino-3-benzylthiopyridine scaffold led to the identification of compound (R)-10b displaying c-Met inhibition with an IC50 up to 7.7nM. In the cytotoxic evaluation, compound (R)-10b effectively inhibited the proliferation of c-Met addictive human cancer cell lines (IC50 from 0.19 to 0.71μM) and c-Met activation-mediated cell metastasis. At a dose of 100mg/Kg, (R)-10b evidently inhibited tumor growth (45%) in NIH-3T3/TPR-Met xenograft model. Of note, (R)-10b could overcome c-Met-activation mediated gefitinib-resistance, which indicated its potential use for drug combination. Taken together, 2-amino-3-benzylthiopyridine scaffold was first disclosed and exhibited promising pharmacological profiles against c-Met, which left room for further exploration.

Palladium-Catalyzed Ortho-Alkoxylation of N-Benzoyl α-Amino Acid Derivatives at Room Temperature

An efficient palladium-catalyzed ortho-alkoxylation of N-benzoyl α-amino acid derivatives at room temperature has been explored. This novel transformation, using amino acids as directing groups, Pd(OAc)2 as catalyst, alcohols as the alkoxylation reagents, and PhI(OAc)2 as the oxidant, showed wide generality, good functional tolerance, and high monoselectivity and regioselectivity.

Ruthenium(II)-Catalyzed Redox-Neutral [3+2] Annulation of Indoles with Internal Alkynes via C–H Bond Activation: Accessing a Pyrroloindolone Scaffold

Ru(II)-catalyzed redox-neutral [3+2] annulation reactions of N-ethoxycarbamoyl indoles and internal alkynes via C-H bond activation are reported. This method features a broad internal alkyne scope, including various aryl/alkyl-, alkyl/alkyl-, and diaryl-substituted alkynes, good to excellent regioselectivity, diverse functional group tolerance, and mild reaction conditions. The N-ethoxycarbamoyl directing group, temperature, CsOAc, and ruthenium catalyst proved to be crucial for conversion and high regioselectivity. Additionally, preliminary mechanistic experiments were conducted, and a possible mechanism was proposed.

Cobalt-catalyzed C(sp3)–H/C(sp2)–H oxidative coupling between alkanes and benzamides

A direct cobalt-catalyzed oxidative coupling between C(sp2)–H in unactivated benzamides and C(sp3)–H in simple alkanes, ethers and toluene derivatives was explored. This protocol achieves direct C–C formation without using alkyl or aryl halide surrogates and exhibits high practicality with ample substrate scope. The method provides a new way to construct linear and five- or six-membered ring moieties in bioactive molecules.

Pd(II)-catalyzed direct functionalization of C–H bonds of benzamides for synthesis of 1,1-difluoro-1-alkenes

Pd-catalyzed direct difluoroallylation of C–H bonds of benzamides with readily available Rf-Br reagents is reported. The reaction proceeds via Pd-catalyzed C–H activation, followed by reaction of the resulting intermediate with 3-bromo-3,3-difluoropropene (BDFP) in a γ-selective fashion. The C–H functionalization process was characterized by a broad substrate scope as well as an excellent functional-group tolerance.

Regio-selective and stereo-selective hydrosilylation of internal alkynes catalyzed by ruthenium complexes

In this study, ruthenium(II)-catalyzed direct hydrosilylation of internal alkynes with high regio-selectivity and stereo-selectivity is reported. This title transformation led to various vinylsilanes in good to excellent yields. This approach features mild reaction conditions, low catalyst loading, air-stability, and good functional group tolerance. Furthermore, gram-scale preparation and some transformations of vinylsilanes were carried out, which further underscored its synthetic utility and applicability.

Cobalt(III)-catalyzed site-selective C–H amidation of pyridones and isoquinolones

In this study, Cp*Co(III)-catalyzed site-selective amidation of pyridones and isoquinolones using oxazolones as the amidation reagent is reported. This approach features mild conditions, high efficiency and good functional tolerance. Furthermore, gram-scale preparation and preliminary mechanism experiments were carried out. It provides a straightforward approach for the direct modification of pyridone derivatives.