Mild copper-mediated fluorination of aryl stannanes and aryl trifluoroborates.

This communication describes a mild copper-mediated fluorination of aryl stannanes and aryl trifluoroborates with N-fluoro-2,4,6-trimethylpyridinium triflate. This protocol demonstrates broad substrate scope and functional group tolerance, and does not require the use of any noble metal additives. The reaction is proposed to proceed via an arylcopper(III) fluoride intermediate.

Cu(OTf)2-mediated fluorination of aryltrifluoroborates with potassium fluoride.

This Communication describes the Cu(OTf)2-mediated fluorination of aryltrifluoroborates with KF. The reaction proceeds under mild conditions (at 60 °C over 20 h) and shows a broad substrate scope and functional group tolerance. The Cu is proposed to play two separate roles in this transformation: (1) as a mediator for the aryl­F coupling and (2) as an oxidant for accessing a proposed Cu(III)(aryl)(F) intermediate.

Merging visible-light photocatalysis and transition-metal catalysis in the copper-catalyzed trifluoromethylation of boronic acids with CF3I.

This communication describes the development of a mild method for the cross-coupling of arylboronic acids with CF(3)I via the merger of photoredox and Cu catalysis. This method has been applied to the trifluoromethylation of electronically diverse aromatic and heteroaromatic substrates and tolerates many common functional groups.

Mechanistic and computational studies of oxidatively-induced aryl-CF3 bond-formation at Pd: rational design of room temperature aryl trifluoromethylation.

This article describes the rational design of first generation systems for oxidatively induced Aryl-CF(3) bond-forming reductive elimination from Pd(II). Treatment of (dtbpy)Pd(II)(Aryl)(CF(3)) (dtbpy = di-tert-butylbipyridine) with NFTPT (N-fluoro-1,3,5-trimethylpyridinium triflate) afforded the isolable Pd(IV) intermediate (dtbpy)Pd(IV)(Aryl)(CF(3))(F)(OTf). Thermolysis of this complex at 80 °C resulted in Aryl-CF(3) bond-formation. Detailed experimental and computational mechanistic studies have been conducted to gain insights into the key reductive elimination step. Reductive elimination from this Pd(IV) species proceeds via pre-equilibrium dissociation of TfO(-) followed by Aryl-CF(3) coupling. DFT calculations reveal that the transition state for Aryl-CF(3) bond formation involves the CF(3) acting as an electrophile with the Aryl ligand serving as a nucleophilic coupling partner. These mechanistic considerations along with DFT calculations have facilitated the design of a second generation system utilizing the tmeda (N,N,N',N'-tetramethylethylenediamine) ligand in place of dtbpy. The tmeda complexes undergo oxidative trifluoromethylation at room temperature.

Oxidation of a cyclometalated Pd(II) dimer with "CF3+": formation and reactivity of a catalytically competent monomeric Pd(IV) aquo complex.

The reaction of [(bzq)Pd(OAc)](2) (bzq = benzo[h]quinoline) with "CF(3)(+)" reagents to afford the monomeric Pd(IV) aquo complex (bzq)Pd(CF(3))(OAc)(2)(OH(2)) is demonstrated. Heating this Pd(IV) adduct at 60 °C for 12 h leads to highly chemoselective aryl-CF(3) bond-forming reductive elimination. The rate and yield of this transformation are both significantly enhanced by the addition of Brønsted and Lewis acidic additives. The mechanism of C-CF(3) bond formation from (bzq)Pd(CF(3))(OAc)(2)(OH(2)) has been studied, and the major pathway is proposed to involve pre-equilibrium acetate dissociation followed by C-CF(3) coupling. Finally, this monomeric Pd(IV) complex is shown to be a kinetically competent intermediate for C-H trifluoromethylation with "CF(3)(+)" reagents. Collectively, these studies provide valuable insights about the speciation, nuclearity, and reactivity of Pd intermediates in catalytic C-H trifluoromethylation reactions.

A unified strategy to reverse-prenylated indole alkaloids: total syntheses of preparaherquamide, premalbrancheamide, and (+)-VM-55599.

A full account of our studies toward reverse-prenylated indole alkaloids that contain a bicyclo[2.2.2]core is described. A divergent route is reported which has resulted in the synthesis of preparaherquamide, (+)-VM-55599, and premalbrancheamide. An intramolecular Dieckmann cyclization between an enolate and isocyanate was used to forge the bicyclo[2.2.2]diazaoctane core that is characteristic of these molecules. The pentacyclic indole scaffold was constructed through a one-pot Hofmann rearrangement followed by Fischer indole synthesis. The utilization of our previously reported indole peripheral functionalization strategy also led to natural products including malbrancheamides B, C, stephacidin A, notoamides F, I and R, aspergamide B, and waikialoid A. Ultimately, the divergent route that we devised provided access to a wide range of prenylated indole alkaloids that are differently substituted on the cyclic amine core.

Investigations into Transition Metal Catalyzed Arene Trifluoromethylation Reactions.

Trifluoromethyl-substituted arenes and heteroarenes are widely prevalent in pharmaceuticals and agrochemicals. As a result, the development of practical methods for the formation of aryl-CF3 bonds has become an active field of research. Over the past five years, transition metal catalyzed cross-coupling between aryl-X (X = halide, organometallic, or H) and various "CF3" reagents has emerged as a particularly exciting approach for generating aryl-CF3 bonds. Despite many recent advances in this area, current methods generally suffer from limitations such as poor generality, harsh reaction conditions, the requirement for stoichiometric quantities of metals, and/or the use of costly CF3 sources. This Account describes our recent efforts to address some of these challenges by: (1) developing aryl trifluoromethylation reactions involving high oxidation state Pd intermediates, (2) exploiting AgCF3 for C-H trifluoromethylation, and (3) achieving Cu-catalyzed trifluoromethylation with photogenerated CF3•.

Practical method for the Cu-mediated trifluoromethylation of arylboronic acids with CF3 radicals derived from NaSO2CF3 and tert-butyl hydroperoxide (TBHP).

A mild and practical protocol for the copper-mediated trifluoromethylation of aryl and heteroaryl boronic acids using NaSO(2)CF(3) (Langlois' reagent) and TBHP is described. The reaction proceeds at room temperature under ambient conditions, and the products can be readily purified by extraction or column chromatography.

Silver-mediated trifluoromethylation of arenes using TMSCF3.

The silver-mediated C-H trifluoromethylation of aromatic substrates using TMSCF(3) is described. The development, optimization, and scope of these transformations are reported. AgCF(3) intermediates are proposed.

3D-QSAR study of corticotropin-releasing factor 1 antagonists and pharmacophore-based drug design.

Corticotropin-releasing factor (CRF) is a neuropeptide that falls into the broad spectrum of having neurotransmitter/neurohormonal/neuromodulator activities. The design and synthesis of low molecular weight non-peptide antagonists for the CRF receptors is a very important area of research as they can be employed in the treatment of a wide variety of disorders. To investigate the ligand-receptor binding mode and design novel CRF1 antagonists, both quantitative and qualitative 3D-QSAR analysis have been performed on a data set of CRF(1) antagonists by using HypoGen and HipHopRefine programs of Catalyst software. The training set of HypoGen study included twenty-five structurally diverse CRF(1) antagonists with Ki values ranging from 0.5 nM to 10 microM. The common feature-based 3D-QSAR study used eight highly potent CRF(1) antagonists and four poor antagonistic ligands to generate 3D-pharmacophore models with excluded volumes. The obtained 3D-pharmacophore models from each study served as queries for virtual screening with a 'focused compound library' for novel CRF(1) antagonist development. Pharmacophore models obtained for antagonist binding are useful for CRF related chemical biology and drug design. Strategies and methods employed in this paper are simple and practical for medicinal chemists in drug R&D.

3D pharmacophore based virtual screening of A 2A adenosine receptor antagonists.

A(2A) adenosine receptor (A(2A)AR) antagonists are considered to be useful in cancer immunotherapy and vaccines and as potential drugs for the treatment of Parkinson's disease. To better understand the chemical features responsible for the recognition mechanism and the receptor-ligand interaction, we performed the molecular docking study using selective A(2A)AR antagonists and combined with a pharmacophore based virtual library screening. The putative binding mode for the antagonists served as the templates for pharmacophore modeling and a virtually generated library have been screened for novel A(2A)AR antagonist development.