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Noteworthy Chemistry

March 4, 2013

Here is an ethylene equivalent for Diels–Alder reactions. The Diels–Alder reaction is one of the best-known and widely used methods for forming cyclohexene derivatives. The reaction usually involves a diene and a dienophile (an olefin that contains an electron-withdrawing group), but an unsubstituted ethylene unit is often needed. The direct use of ethylene, however, often requires harsh reaction conditions.

Although several ethylene equivalents have been developed for Diels–Alder reactions, reactants that give higher yields with fewer limitations are needed. M. E. Jung and colleagues at the University of California, Los Angeles, report that phenyl selenoacrylate (1) is a good dienophile whose Diels–Alder adducts are easily converted to diene–ethylene products.


Compound 1 can be synthesized in two steps from propargyl alcohol: a Cu(I)-catalyzed phenylselenylation followed by a Meyer–Schuster rearrangement in the presence of TsOH·H2O. (TsOH is p-toluenesulfonic acid.) The overall yield is 59%. An alternative one-step preparation gives 1 in 34% yield from acryloyl chloride and phenylselenocopper.

The authors carried out Diels–Alder cycloadditions of 1 with various diene substrates. All products (represented by 2) were obtained in good yield (66−97%). Whereas 1 exhibits great regioselectivity toward dienes, it often gives mixtures of endo and exo isomers because of its poor stereoselectivity.

The phenylseleno group is removed by reducing 2 with tris(trimethylsilyl)silane [(Me3Si)3SiH, 2 equiv] and azoisobutyronitrile (AIBN, 0.2 equiv) in isooctane or toluene solvent. The yields of cyclohexene 3 were 63–99%.

The authors believe that the reduction proceeds via a radical process (see figure). In their mechanism, acyl radical 4 generated from 2 and (Me3Si)3Si· is decarbonylated to give 5, which forms 3 by reacting with (Me3Si)3SiH. A potentially competitive process that produces aldehyde 6 was not observed.

The authors demonstrated the practicality of using 1 for Diels–Alder reactions in the total synthesis of brasilicardin A, a naturally occurring immunosuppressant. They converted a diene intermediate to the corresponding ethylene-added cycloalkene in 66% yield. (Angew. Chem., Int. Ed. 2013, 52, 2060–2062; Xin Su)

Make functional, fluorescent poly(methacrylic acid) nanoparticles. L. Wang and B. C. Benicewicz* at the University of South Carolina (Columbia) synthesized poly(methacrylic acid) (PMAA)–functionalized silica nanoparticles labeled with a fluorescent dye. They used a reversible addition–fragmentation chain-transfer agent to initiate the living radical polymerization of methacrylates and achieve high grafting densities on dye-labeled silica nanoparticles.

The authors first grafted tert-butyl methacrylate onto surface amine–decorated silica nanoparticles in THF solvent. They then deprotected the polymethacrylate ester by treating it with Me3SiBr to form PMAA-grafted, dye-labeled silica nanoparticles.

The authors then developed a more robust, simpler sequence with DMF as the solvent. MAA was polymerized directly onto coated silica nanoparticles as small as 15 nm diam to produce well-dispersed, stable 30-nm diam nanoparticles with low-polydispersity, ≈41-kDa grafted PMMA chains. These synthetic pathways combine detectible labeling and functional nanoparticle grafts for several biomedical applications. (ACS Macro Lett. 2013, 2, 173–176; LaShanda Korley)

Aggregation induces emission from a TCAQ fluorogen. Many fluorogens with strong solid-state emissions are available, but solid-state fluorogens that emit efficiently in the long-wavelength region are rare. H. Dong, W. Hu, and co-workers at the Chinese Academy of Sciences (Beijing) report a TCAQ-based fluorogen with yellow emission in the aggregated state. (TCAQ is 11,11,12,12-tetracyano-9,10-anthraquinodimethane, a highly conjugated molecule that is used as an electrically conducting material and a donor–acceptor system.)

Introducing phenyl rotors to the 2- and 6-positions of TCAQ produces a fluorogen (1) that exhibits aggregation-induced emission enhancement (AIEE). The fluorogen fluoresces weakly as a molecular species, but it is highly emissive as aggregated clusters.

This is the first example of a TCAQ derivative with AIEE properties. The authors attribute the efficient fluorescence of 1 in the aggregated state to restricted rotation of its phenyl rotors caused by multiple intermolecular C–H⋅⋅⋅N bonds. (Chem. Commun. 2013, 49, 1199–1201; Ben Zhong Tang)

Use two statistical techniques for efficient reaction optimization. Optimizing transition metal–catalyzed reactions encompasses many parameters. Several of these, such as solvent and ligand choice, are discrete rather than continuous. With 500 commercially available ligands and 100 possible solvents, the number of permutations is in the millions.

P. M. Murray, S. N. G. Tyler, and J. D. Moseley* at CatScI Ltd. (Cardiff, UK) show that Principal Component Analysis (PCA) allows discrete factors to be treated as continuous parameters. This is done by using appropriate chemical properties of the components as surrogates. Combining PCA with design of experiments (DoE) means that an effective initial screening requires only 35 experiments.

The authors give a worked example in which a Buchwald–Hartwig sulfamidation reaction is optimized to use an inexpensive ligand that has no intellectual property restrictions. (Org. Process Res. Dev. 2013, 17, 40–46; Will Watson)

Make Aerangis lactones stereoselectively in two steps. Continuous-flow reactions and biocatalysis are synthetic techniques that are widely used in laboratory synthesis and industrial production. Combining the techniques can simplify some challenging, arduous synthetic routes.

M. D. Mihovilovic and colleagues at Vienna University of Technology developed an efficient stereoselective synthesis of a lactone in a single operation that integrates continuous-flow reduction with batch biocatalytic oxygenation. The lactone is the main odor component of white orchids of the Aerangis genus. It is used in the fragrance and cosmetics industries.

At least seven steps are required to stereoselectively synthesize the Aerangis lactone [(5S,6S)-1], a method that is not practical for industrial-scale production (Winter, P. et al. Chem. Commun. 2011, 47, 12200−12202). From a two-step nonstereoselective route to the lactone from the inexpensive starting material dihydrojasmone (2) (Kaiser, R. Eur. Patent 513627 [1992]), the authors recognized that stereoselective control of the reduction and oxidation steps would produce (5S,6S)-1 as a single stereoisomer.


The authors first optimized the conditions for the diastereoselective hydrogenation of 2. They found that the two enantiomers of cis-3 can be produced in 93% yield and 100% conversion of 2 when they used 5% Rh/C and Cs2CO3 (1:5 w/w) as the catalyst in a ThalesNano H-Cube continuous-flow hydrogenation reactor (ThalesNano Nanotechnology, Budapest). As much as 121 g/day of 3 could be made in 10-g batches. The direct diastereoselective synthesis of the trans-3 enantiomers was unsuccessful, so the authors epimerized cis-3 to trans-3 almost quantitatively in an Amberlyst 15–packed glass column.

After they obtained the two epimers, the authors sought enzymes to catalyze the diastereoselective oxidation of 3. They converted (2S,3S)-cis-3 to (5S,6S)-1 by using cyclododecanone monooxygenase from Rhodococcus ruber SC1. The non–natural epimer (5R,6S)-1 was produced from (2S,3R)-trans-3 by oxidizing it with cyclopentanone monooxygenase from Comamonas sp. NCIMB 9872. Epimers (2R,3R)-3 and (2R,3S)-3 are not affected by the oxidation enzymes.

In a preparative set-up, the epimers of 3 are not isolated. Both epimers of 1 are obtained in good yield (27–28%) with excellent optical purity and high diastereomeric purity. (ChemCatChem 2013, 5, 724–727; Xin Su)

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