Noteworthy Chemistry

September 17, 2012

Copper-catalyzed aryl halide amination goes green. The preparation of aromatic amines from the corresponding halides has become a relatively mature field of study over the past decade. It is still desirable, however, to develop a recyclable catalyst that can be used with nontoxic solvents. To this end, Y. Wan and coauthors at Sun Yat-sen University (Guangzhou, China) and Hengyang Normal University (China) developed a copper catalyst system that uses sucrose and biodegradable solvents for aminating aryl halides.

The authors used the amination of p-bromoanisole by NH4OH in the presence of CuO and K3PO4 as a model reaction to evaluate the efficiency of a series of carbohydrate-based oxygen-containing ligands. Of the nine mono- and polysaccharides screened, only sucrose had high catalytic efficiency; it produced p-anisidine in 71% yield by GC. The yields from the other ligands were <5%.

X-ray photoelectron spectroscopy showed that Cu(II) was partially reduced to Cu(I) in the glucose–fructose system. Poly(ethylene glycol) (PEG) was selected over n-Bu4NBr as the phase-transfer catalyst for environmental reasons.

After they identified sucrose as the ideal ligand, the authors continued to optimize the reaction conditions. They found that CuSO4 is the most efficient Cu(II) source and that KOH and K3PO4 are efficient bases. K3PO4, however, causes less glassware corrosion.

When the reagents and reaction conditions were 0.2 equiv CuSO4 and 1 equiv K3PO4 in a 1:1 w/w mixture of PEG-200 and water at 90 °C for 15 h, p-bromoanisole conversion was almost quantitative (99%), and the p-anisidine yield was 88%. These optimal conditions worked well for a broad range of bromo- and iodoarenes with yields of 60−85%. Even normally unreactive o-iodonitrobenzene gave 78% of the nitroaniline. The reaction, however, does not work for chloroarenes. (Eur. J. Org. Chem. 2012, 4897–4901; Xin Su)

Use gentle agitation to form biocompatible hydrogels. M. L. Becker and colleagues at the University of Akron (OH) used mechanical strain to induce poly(ethylene glycol) (PEG)–derived hydrogels to cross-link. Specifically, the copper-free cycloaddition of equimolar amounts of glycerol exytholate triazide and PEG functionalized with 4-dibenzocyclooctynol yielded hydrogels within 5 min under gentle mechanical agitation.

With the goal of injectable delivery for biomedical applications, the authors determined that strain-dependent gelation occurs in ≈1000 s, with complete cross-linking within 2.5 h. They showed that cell-encapsulated hydrogels are biocompatible and emphasized their potential as versatile biomaterials platforms. (ACS Macro Lett. 2012, 1, 1071–1073; LaShanda Korley)

Prepare chiral aminonitriles with a modified Strecker reaction. α-Aminonitriles are useful intermediates for preparing amino acids. The usual way to make them is the Strecker reaction—the addition of cyanide to imines. When chiral amino acids are needed, enzymes, metal complexes, or organocatalysts are used. N.-u. H. Khan and co-workers at the Central Salt and Marine Chemicals Research Institute (Gujarat, India) report the enantioselective addition of cyanide to iminium salts prepared in situ.

The salts are generated by the reaction of aliphatic or aromatic aldehydes with secondary amines such as morpholine (1) or 4,5,6,7-tetrahydrothieno[3,2-c]pyridine (2). They then react with Me3SiCN in the presence of quinine derivatives to give chiral α-aminonitriles (3 and 4) in up to 95% yield and 94:6 er.

A key to maximizing yields is the addition of NaF to polarize the Si–CN bond and facilitate cyanide transfer to the iminium salts. Another improvement is to substitute hydroquinine for quinine as the chiral catalyst.

When 2-chlorobenzaldehyde is used as the starting material, the product (5) is an intermediate in the synthesis of the antiplatelet agent (S)-clopidogrel. (J. Org. Chem. 2012, 77, 7076–7080; JosÉ C. Barros)

A more active catalyst gives a greener process. Meerwein–Ponndorf–Verley (MPV) reduction reactions that use Al(O-i-Pr)3 as the catalyst in i-PrOH solvent are often slow. As much as 50 mol% catalyst may be needed to achieve reasonable reaction times.

C. L. Liotta and coauthors at Georgia Tech (Atlanta) and American Pacific Corporation—Fine Chemicals (Rancho Cordova, CA) studied MPV reductions with Al(O-t-Bu)3 as the catalyst. They used three model substrates: PhCHO, Ph2CO, and N-(tert-butoxycarbonyl)-(3S)-3-amino-1-chloro-4-phenyl-2-butanone, an industrially important intermediate for synthesizing HIV protease inhibitors. In all cases, reactions using 50 mol% Al(O-t-Bu)3 were significantly faster than the equivalent reactions with Al(O-i-Pr)3.

For example, the PhCHO reduction was complete in 20 min with Al(O-t-Bu)3, whereas the Al(O-i-Pr)3 reduction reached only 30% conversion in that time. The greater activity makes it possible to reduce the catalyst loading to 20 mol% without a significant increase in reaction time; it also reduces the amount of aluminum salts in the waste stream. The reaction can be carried out in mixed solvent systems such as 9:1 v/v toluene–i-PrOH. The authors attribute the difference in catalyst activity to differences in the aggregation states of the two catalysts. (Org. Process Res. Dev. 2012, 16, 1301–1306; Will Watson)

Annulated metalloles are efficient luminophores. Nonannulated metalloles such as 1 are often nonluminescent in the solution state even when they are highly emissive in the solid state. T. Yasuda, C. Adachi, and coauthors at Kyushu University (Fukuoka, Japan) and the Japan Science and Technology Agency (Tokyo) developed a family of annulated metalloles with heteroatom bridges (2) that luminesce efficiently in the solution and solid states with fluorescence quantum yields (ΦF) of up to 94%.

The nonbridged parent form (3) of 2 is much less fluorescent with ≤18% ΦF. The high ΦF values of fluorophores 2 therefore must be a result of suppression of the intramolecular rotation of their central thiophene rings by heteroatom annulation. The ΦF values of 2 in the solid state are higher than those of their solutions, probably because the intramolecular rotation of their peripheral phenyl rings is more restricted by the physical constraints of the solids.

An electroluminescence device in which sulfone derivative 4 is the emitting species has an extremely high external quantum efficiency (6.1%), low turn-on voltage (2.8 V), and high brightness (46,300 cd/m2). These values show that annulated metalloles have great potential for high-tech applications. (J. Mater. Chem. 2012, 22, 16810–16816; Ben Zhong Tang)

Olfaction mediates nematode interactions. Parasitic nematodes seek out hosts in which to complete their lifecycles. Olfaction is one of the sensory methods they use in this complex process, which is called chemotaxis. P. W. Steinberg, E. A. Hallem, and coauthors at Caltech (Pasadena, CA) and the University of California, Los Angeles studied the olfactory responses of several entomopathogenic nematode (EPN) species to invertebrate hosts.

The authors chose six EPNs—parasites that infect and kill insect larvae—because they are easy to study in laboratory, resemble human-parasitic nematodes, and can be used as environmentally safe insecticides. They used seven potential EPN hosts: house cricket, mole cricket, earwig, flatheaded borer, waxworm, pillbug, and slug.

The authors first investigated the effect of CO2 as a universal host cue. For all of the host species, the degree of attraction correlated with CO2 concentration. In the presence of soda lime, which absorbs CO2, chemotaxis is reduced for all EPN–host combinations.

Next, 21 odorants released by potential hosts that could attract EPNs were identified by solid-phase microextraction–GC-MS or thermal desorption–GC-MS. With the exception of slugs, all hosts released at least one odorant. Most EPN species exhibited specific responses to odorants, and the responses were dose-dependent. A better understanding of the odorants involved (alone or combined with CO2) is crucial for modeling EPN–host interactions and developing new biocontrol agents. (Proc. Nat. Acad. Sci. U.S.A. 2012, 109, E2324–E2333; JosÉ C. Barros)

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