Noteworthy Chemistry

February 7, 2011

A magnetically recoverable catalyst converts imines to alkynes. G. Song, C. J. Li, and coauthors at East China University of Science and Technology (Shanghai) and McGill University (Montreal) used magnetic Fe3O4 (magnetite) nanoparticles with SiO2 shells as a support for magnetically recoverable catalysts. They attached the nanoparticles covalently to a chiral Cu(I) complex to form magnetic catalyst system 1. This catalyst mediates the enantioselective reaction of imines and anilines to form terminal alkynes under mild conditions.

The authors coated commercially available magnetite nanoparticles (<50 nm diam) with a silica layer to form core–shell particles (2). Treating the particles with 3-aminopropyltriethoxysilane provides amine-functionalized silica nanoparticles (3) with a convenient point for attaching chiral ligand 4, which is readily prepared from a commercially available compound. (BINOL is 1,1′-binaphthyl-2,2′-diol.) The resulting nanoparticle-supported ligand 5 is treated with a CuOSO2CF3–toluene complex to form the target catalyst complex 1. Electron microscopy confirmed that the particle morphology of 1 consisted of small Fe3O4 nanoparticle clusters encapsulated in the silica shell.

The authors assessed the catalytic efficiency of 1 by using it to promote the addition of aniline derivatives to a series of imines to form terminal alkynes. A typical reaction leads to the desired propargylamine adduct in 92% yield with 92% ee. The catalyst can be recovered by decanting the reaction mixture in the presence of an external magnet. Catalyst 1 can be recycled more than six times without significant loss in activity or enantioselectivity.

The authors note that no other example of this magnetic nanoparticle-supported copper–ligand complex has been reported. (Org. Lett. 2011, 13, 442–445; W. Jerry Patterson)

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Improve a palladium-catalyzed cyanation by adding zinc acetate. Palladium-catalyzed cyanations of 5-chloropyrazinones are rare because of the substrates’ low reactivity. While improving a cyanation step in the synthesis of two corticotropin-releasing factor antagonists, D. K. Leahy and co-workers at Bristol-Myers Squibb (New Brunswick, NJ, and Wallingford, CT) used a [1,1’-bis(diphenylphosphino)ferrocene]palladium catalyst with Zn(CN)2 and zinc dust reagents. Conversion was complete, but 0.6% of a dechlorinated impurity was produced. In an effort to eliminate the impurity, the authors used ZnBr2 as an additive, but the impurity level increased instead.

Using Zn(OAc)2 as the additive, however, reduced the impurity level to 0.1%. In contrast to ZnBr2, which accelerates cyanation reactions, adding Zn(OAc)2 reduces the reaction rate. (Org. Process Res. Dev. 2010, 14, 1221–1228; Will Watson)

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Grow vinyl chloride units from a vanadium catalyst. Coordination polymerization is a major advance in polymer chemistry. Coordination between organometallic compounds and double bonds allows vinyl monomer units to be added to the reactive center. Until now, usable monomers have been restricted to nonpolar olefins such as ethylene, propylene, and styrene. The principal challenge to the homo- and copolymerization of polar monomers is catalyst poisoning. The polar groups can bind to the metal center to block olefin coordination and hinder monomer insertion.

Y. Tsuchiya and K. Endo at Osaka City University (Japan) explored the application of organovanadium catalysts in the homo- and copolymerization of polar monomers. They selected vinyl chloride (VC) as the monomer because its polymer is a commercially important material with chemical and biological resistance. Catalyst 1, vanadium tris(acetylacetonate), does not coordinate the double bond in VC and therefore does not catalyze homopolymerization. In combination with i-Bu3Al, however, catalyst 2, vanadium oxytriethoxide, can initiate the propagation of VC units. Moreover, copolymerization of VC with styrene, 1-butene, methyl methacrylate, or methyl acrylate proceeds smoothly. The authors state that the detailed mechanism requires further investigation. (J. Polym. Sci., Part A: Polym. Chem. 2011, 49, 1006–1012; Sally Peng Li)

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Purify nanotubes by ultrasonication. D. S. Su and co-workers at the Fritz Haber Institute of the Max Planck Society (Berlin) explored ultrasonication as a technique for purifying carbon nanotubes (CNTs). They used the method on two CNT systems: pristine multiwalled CNTs (pCNTs) with a random amorphous carbon monolayer (carbon purity 95 wt%, ~10 nm outer diam) and the same CNTs oxidized with HNO3 (oCNTs).

Pulsed sonication of pCNTs increased their oxidative stability and removed metal precursors without damaging the CNT surfaces. Raman spectroscopy confirmed an increase in graphitic ordering with ultrasonic treatment. The oxidative process induced by mild HNO3 treatment makes it easier to remove the amorphous carbon coating, but it leads to significant structure defects and debris on the CNT surface and tip opening, and it produces higher intensity UV–vis absorption.

The authors propose that oxidation is not the dominant mode for CNT purification and that the character of the sonication solvent can modulate the extent of purification. Ultrasonication of oCNTs improved their oxidative stability and promoted removal of surface products. This research demonstrates the utility of sonication as a simple and effective strategy for CNT purification without surface damage and structural alteration. (Chem. Mater. 2011, 23, Article ASAP cm103069z; LaShanda Korley)

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Make a potent reuptake inhibitor by enyne cycloisomerization. V. I. Elitzin and co-workers at GlaxoSmithKline (Research Triangle Park, NC) previously developed a first-generation route to racemic mixture 1, a highly effective serotonin, epinephrine, and dopamine reuptake inhibitor (Elitzin, V. I. et al. Org. Process Res. Dev. 2010, 14, 912–917). Whereas this method can be used on a multikilogram-scale, it has several limitations, including the formation of highly undesirable polychlorinated biphenyls (PCBs), expensive reaction ingredients, and low atom efficiency. The authors report an improved alternative synthesis of 1 that features a highly selective transition metal–catalyzed enyne cycloisomerization as one of the key steps.

Low-cost propargylamine (2) and arylsulfonyl chloride 3 react to form the o-nitrosulfonyl (nosyl) N-protecting group in 4. Sonogashira coupling with the appropriate aryl iodide leads to 5 with no detectable PCBs in the reaction products. Allylation with 6 gives the desired cycloisomerization precursor 7, which undergoes platinum-mediated cyclization to form key bicyclic enamine 8. Reducing the enamine function gives amine 9, and the nosyl protecting group is removed to produce target compound 1. The synthesis has a high 58% overall yield.

The authors evaluated synthetic methods that promote enantioselective cycloisomerization of 7. Their efforts resulted in 59% ee at best, but further process optimization may produce 1 with high enantioselectivity. (J. Org. Chem. 2011, 76, 712–715; W. Jerry Patterson)

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Inspect the mother liquors from a classical kinetic resolution to determine whether a dynamic resolution is possible. In the course of improving the process for making casopitant methanesulfonate, a central nervous system–active drug, F. Bravo and co-workers at GlaxoSmithKline R&D (Verona, Italy) resolved racemic 2-(4-fluoro-2-methylphenyl)-4-piperidone with 0.5 equiv (S)-mandelic acid. Classical kinetic resolution led to the crystallization of the desired (R)-enantiomer of the piperidone mandelate salt.

The mother liquors from the resolution should have been enriched in the piperidone (S)-enantiomer, but they contained both enantiomers in a ~1:1 ratio because the conditions caused the (S)-enantiomer to epimerize. This serendipitous result led the authors to develop a dynamic kinetic resolution technique in which the driving force of the crystallization is used to enhance product purity. (Org. Process Res. Dev. 2010, 14, 1162–1168; Will Watson)

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Use water-tolerant alkylindium reagents in palladium chemistry. Organoindium reagents are usually more tolerant to functional groups than the corresponding magnesium or zinc compounds. Current routes to these compounds are the reactions of RMgX or RLi with indium halides under anhydrous conditions. T.-P. Loh and co-workers at Nanyang Technological University (Singapore) developed a direct preparation of alkylindium reagents from alkyl halides.

Using the reaction between 2-iodoethylbenzene (1) and metallic indium in THF at room temperature as a model, the authors found that CuCl is the best copper catalyst for the reaction. The reaction tolerates the presence of water and air, but the indium reagents are unstable toward purification over silica gel. Although the exact nature of the alkylindium product (2) is not fully understood (X1 can be iodide, a copper anion, or both), there is only one compound, as opposed to the two products from the reaction between halides and indium mediated by LiCl.

The organoindium compound was used in palladium-catalyzed C–C coupling with aryl halides, preferably iodides or bromides. (DMA is N,N-dimethylacetamide.) The results showed good yields and tolerance to functional groups such as hydroxyl, nitrile, ester, and carbonyl. Less reactive aryl bromides and chlorides were also coupled in moderate yields, as were heteroaryl halides.

Expansion of the method to other alkylindium compounds reinforced the robustness of this reaction. When the solvent is changed from THF to DMA and the temperature raised to 100 °C, the preparation of alkylindium compounds from alkyl bromides proceeds with higher yields. This method is quite general, shows great reagent compatibility, and does not require special care with respect to solvents or atmosphere. (Angew. Chem., Int. Ed. 2011, 50, 511–514; José C. Barros)

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