Noteworthy Chemistry

February 14, 2011

Form β-heteroaryl ketones directly from propargylic ketones by using a tandem catalytic process. Naturally occurring and bioactive compounds that contain a functionalized heteroarene scaffold are major synthetic targets. Heteroaromatic structures are typically prepared by Friedel–Crafts alkylation, which usually requires electrophiles to be prepared in a separate operation.

B. M. Trost* and A. Breder at Stanford University (CA) believed that forming the desired electrophile and running the subsequent SEAr reaction under identical conditions would be a significant improvement to this synthetic method. They combined ruthenium-catalyzed redox isomerization of propargyl alcohols with the Friedel – Crafts conjugate addition. They carried out a direct, regioselective, high-yield synthesis of β-heteroaryl ketones from propargyl alcohols with this tandem sequence.

In a typical procedure, alkynol 1 is treated with ruthenium catalyst complex 2, indium trifluoromethanesulfonate, and (R)-camphorsulfonic acid (CSA) at elevated temperature. Adding the desired heteroarene 3 at room temperature gives the corresponding ketone 4. Similarly, 5 and 6 react to produce ketone 7. Electron-rich or neutral heteroarenes give up to 97% product yields, but electron-deficient analogues fail to react, highlighting the chemoselectivity of the catalyst system.

A key aspect of the procedure is the capability of the catalyst system to promote redox isomerization of the alkynol and 1,4-addition of the heteroarene to make simple enones under mild conditions. They stress the advantage this method offers for synthesizing α,β-unsaturated carbonyl compounds, a method that usually relies on somewhat wasteful olefination reactions with phosphorus ylides.

An asymmetric version of this procedure, currently being studied, would increase its synthetic value substantially. (Org. Lett. 2011, 13, 398–401; W. Jerry Patterson)


Gold mine: Biological templates meet metal deposition. Y. He, A. E. Ribbe, and C. Mao* at Purdue University (West Lafayette, IN) generated a nanostructured array of discrete gold nanoparticles by using a 2-D DNA template and thermal evaporation of gold metal. They controlled the gold nanoparticle pattern (hexagonal and tetragonal arrays) independently of the nanoparticle size by their selection of complex DNA templates and the amount of deposited gold clusters (0.8-nm thick layer and ~4 ± 2 nm diam vs 3-nm layer and ~9 ± 3 nm diam).

The authors describe this production strategy as a method for generating functional metallic arrays with controlled architectures and nanoparticle sizes for advanced electronic applications. (J. Am. Chem. Soc. 2011, 133, 1742–1744; LaShanda Korley)


Use a copper tube to catalyze continuous-flow reactions. Continuous-flow chemical synthesis has several advantages over batch conditions: efficient mixing, improved safety from better control of reaction parameters, and easy scale-up. N. Mainolfi and coauthors at the Novartis Institutes for Biomedical Research and MIT (both in Cambridge, MA) used a copper tube flow reactor (CTFR) in place of copper compounds to catalyze reactions.

The CTFR system (C in the figure) consists of a coil of copper tubing (A) that can be inserted into a glass jacket to allow heating to 150 °C or into a metal jacket for heating to 250 °C (B).

The authors first evaluated an Ullmann coupling between PhI and BzNH2 at 120 °C. The copper tube was superior to a perfluoroalkoxyalkane tube, standard reflux, or microwave conditions. Important parameters to be optimized were residence time and flow rate; the best conditions gave a quantitative conversion to BzNHPh. Reactions between other halides and amines worked equally well. QuadraPure thiourea resin was used to remove traces of copper in all reactions in copper tubes.

Next, the authors carried out Sonogashira couplings between haloarenes and alkynes at 120 °C in the presence of Bu4NOAc in DMF solvent. Other commonly used bases such as Et3N or solvents such as MeCN caused precipitation and blockage of the system. Most yields were >85%, but less-reactive alkynes such as Me3SiC≡CH required 0.5 mol% of Pd(PPh3)2Cl2 as a cocatalyst. No alkyne homocoupling (Glaser or Hay reaction) was detected with this procedure, presumably because of the low residence time of the reactants in the copper tube.

Finally, the protiodecarboxylation of aromatic carboxylic acids to unsubstituted aromatics was tested at 250 °C in N-methylpyrrolidone solvent. Excellent yields were obtained even in the absence of additives and ligands. The generation of CO2 from the reaction mixture was not a safety concern because only a small amount of gas was generated at any time. In summary, this method permits safe copper-mediated reactions in which the reaction tube is the catalyst. (Org. Lett. 2011, 13, 280–283; Jose C. Barros)


Less AZADO than TEMPO is needed in an alcohol oxidation. During the process development of an NK1-II inhibitor, M. E. Kopach and co-workers at Eli Lilly (Indianapolis and Kinsale, Ireland) used catalytic amounts of TEMPO as the primary oxidant in the pilot plant–scale oxidation of (2-chlorophenyl)[2-(benzenesulfonyl)pyridin-3-yl]methanol to the corresponding ketone. (TEMPO is the stable oxygen radical 2,2,6,6-tetramethylpiperidine-N-oxyl.) The reaction required 7 mol% TEMPO for full conversion.

Because TEMPO is expensive, other oxidation catalysts were screened during the development of a second-generation process. Various TEMPO derivatives and AZADO (2-azaadamantane-N-oxyl) performed similarly at 7 mol% catalyst loading. The AZADO catalyst loading could be reduced to 0.5–1 mol% without loss in yield. (Org. Process Res. Dev. 2010, 14, 1229–1238; Will Watson)


Alkylation activates luminescence through cation–π interactions. Chemical reactions can affect light emission by different processes and mechanisms, such as attaching a new group, breaking an existing bond, altering molecular conformations, and extending electronic conjugation. S. D. Bull, J. S. Fossey, and coauthors at the University of Birmingham (UK), the School of Organic and Mineral Chemistry (Compiègne, France), the University of Bath (UK), and Ochanomizu University (Tokyo) developed a chemical sensing system in which the fluorescence response to alkylating agents is triggered by a unique cation–π interaction.

4-(3-Phenylpropyl)pyridine (1) is a nonconjugated molecule and therefore nonfluorescent. Its emission can be “turned on” by an alkyl halide such as MeI, with emission enhancement up to two orders of magnitude. This is a simple, robust, inexpensive chemosensor for the fluorescent detection of a range of common alkylating agents. The authors believe that the cation–π interaction within the 1-alkyl-4-(3-phenylpropyl)pyridinium salt (2) is responsible for the fluorescence turn-on process. (Chem. Commun. 2011, 47, 253–255; Ben Zhong Tang)


Make 3-D nanoporous networks from a triblock copolymer. Copolymerization is a useful technique for covalently binding chemically incompatible segments along a polymer backbone. The different components have a propensity to separate similarly to oil and water. Nanoscale structures that form spontaneously from block copolymers potentially can be used in templates and separation membranes.

K. Loos, G. ten Brinke, and coauthors at the University of Groningen (The Netherlands), ICTM-Center for Catalysis and Chemical Engineering (Belgrade, Serbia), and the Helsinki University of Technology (Espoo, Finland) report a method for producing nanopore networks for nickel deposition.

The authors prepared the triblock copolymer poly(tert-butoxystyrene)–polystyrene–poly(4-vinylstyrene) (P4VP). Then they added a less than stoichiometric amount of pentadecylphenol (PDP), which associates only with the P4VP block by intermolecular interactions. The three blocks phase separate and self-assemble into a bicontinuous double gyroid core–shell morphology with comblike P4VP–PDP channels.

Washing with EtOH removes the PDP and causes the P4VP channels to collapse onto the pore walls and form nanoporous networks. The porous structure can be used as a template for electroless nickel plating. (Macromol. Rapid Commun. 2011, 32, 366–370; Sally Peng Li)


Use a mild, simple method for aryl trifluoromethylation. The presence of the benzotrifluoride group in pharmaceuticals is extremely important, as illustrated by such drugs as celecoxib, fluoxetine, and dutasteride. T. D. Senecal, A. T. Parsons, and S. L. Buchwald* at MIT (Cambridge, MA) developed a simplified route to this structural element by using room temperature copper-mediated oxidative trifluoromethylation of arylboronic acids.

The optimum catalyst system consists of simple, inexpensive Cu(OAc)2 as the copper source and 1,10-phenanthroline as the ligand. Me3SiCF3 serves as an efficient trifluoromethyl group donor, and the reaction is run under oxygen. Product yields are moderate to good (68% at most) from electron-rich or electron-deficient arylboronic acids.

The mild conditions provide high functional group tolerance, as illustrated by boronic acids bearing a tert-butyldimethylsilyl-protected phenol and an N-triisopropylsilyl-protected pyrrole. This degree of functional group compatibility is new for trifluoromethylation chemistry. The trifluoromethylation reaction also works well for heteroarylboronic acids.

The authors’ procedure is amenable to a normal benchtop setup, with inexpensive and air-stable catalysts and a simple oxygen gas purge. (J. Org. Chem. 2011, 76, 1174–1176; W. Jerry Patterson)


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