Noteworthy Chemistry

October 17, 2011

Here is the first regiospecific synthesis of anti-anthradithiophenes. Small, high-purity organic molecules for optoelectronic applications are useful alternatives to polymers, which are difficult to purify and characterize. Some particularly efficient molecular structures are analogues of fused linear acenes that have heteroatoms in their aromatic cores. Anthradithiophene (ADT) derivatives, in particular, are stable to photo-oxidation and have high charge carrier mobilities, typically in the 0.4–6.0 cm2/V·s range.

Y. H. Geerts and coauthors at the Free University of Brussels, Karel de Grote University College (Antwerp, Belgium), and the University of Antwerp observed that mixtures of syn- and anti-ADT isomers have been extensively explored, but the total synthesis of isomerically pure individual ADT derivatives has not been reported. The centrosymmetric ADT anti isomer should have a higher charge carrier mobility (up to 1.5 cm2/V·s) than its axisymmetric syn isomer.

The authors describe the total synthesis of isomerically pure anti-ADT derivatives (1). The syn isomer 2 is shown in the figure for comparison. Structure 1 contains terminal alkyl groups to make them soluble, which aids characterization and device preparation. The authors synthesized products that contain n-hexyl or 3,7-dimethyloctyl groups. The reaction sequence shown was used to prepare the n-hexyl product.

The sequence begins with the bromination of commercially available 2-hexylthiophene with N-bromosuccinimide to form bromo derivative 3. In a separate reaction, dibromide 4 is lithiated and then treated with DMF to yield the corresponding bisaldehyde 5. The lithium salt of 3 is quenched with 5 to make bisdiol 6, which is not purified but reduced to give structure 7.

Formylation at the bromine sites on 7 produces corresponding bisaldehyde 8. Compound 8 is treated with sulfonic acid–functionalized Amberlyst resin, which catalyzes its cyclization to 1,4-hydroquinone 9. Intermediate 9 is the structure preferred by the authors for establishing the anti configuration by 13C NMR and X-ray diffraction analysis. Quinone 9 is easily reduced and ring-aromatized to the desired linear acene 1.

The structure of the pure anti-ATD isomer was confirmed by mass spectroscopy and absorption spectra. This synthetic method can be used to prepare useful quantities of the anti-ADT isomer so that its performance in devices such as field-effect transistors can be determined. (Org. Lett. 2011, 13, 5208–5411; W. Jerry Patterson)

Grow crystallographically oriented, shaped gold microrings. A team of researchers led by J. S. Martinez at Los Alamos National Laboratory (NM) and H. Yoo at Hallym University (Chuncheon, South Korea) developed a strategy to synthesize a new hollow metal nanosystem with oriented crystal growth and micrometer-scale edge lengths. The authors generated gold rings by reducing HAuCl4 with the commercially available polyether surfactant Brij35 in the presence of NaOH. This synthesis does not require a mineral acid, a strongly binding ligand, or a sacrificial template.

The synthesized gold materials have empty spaces within platelike ring morphologies. The authors observed a thin layer or a half-formed hole in many plates when the reaction was incomplete (i.e., heated for <12 h). When the reaction was complete, almost all of the platelike structures had the ring morphology.

This work is the best example of triangular or hexagonal microscale gold rings that can be formed in solution phase without the use of galvanic exchange or lithographic methods. The authors suggest that, in addition to hollow gold structures, this strategy should be an easy way to prepare hollow structures of other metals that will be useful in catalysis and electronics. (Adv. Mater. 2011, 23, 4431–4434; Gary A. Baker)

Use anti-Markovnikov hydration to make primary alcohols. Olefin hydration is an important industrial process for making alcohols. Following the Markovnikov rule, secondary alcohols are usually obtained. Currently, a hydroboration–oxidation sequence that creates significant amounts of boron-containing waste is used to make primary alcohols.

R. H. Grubbs and coauthors at Caltech (Pasadena, CA), King Fahd University of Petroleum and Minerals (Dhahran, Saudi Arabia), and the Institute of Chemical and Engineering Sciences (Jurong Island, Singapore) report an olefin hydration reaction that produces primary alcohols. Their process uses a two-catalyst system in which the oxidation reaction is mediated by palladium, and the reduction reaction is ruthenium-mediated.

The researchers chose styrene as the model substrate to test the two-catalyst system. Its primary alcohol product, 2-phenylethanol (1), is an important ingredient in the flavor and fragrance industries. The Wacker process catalyst PdCl2 is used for the oxidation reaction; the reduction is mediated by Shvo’s catalyst (2). CuCl2 is added to prevent over-reduction to ethylbenzene, and benzoquinone (BQ) is used as a co-oxidant.

Alcohol 1 is produced in 77% yield; the major byproducts are phenylacetaldehyde (1.5%), acetophenone (1.4%), ethylbenzene (1.3%), and 1-phenylethanol (0.7%). This method requires high catalyst loadings and stoichiometric amounts of benzoquinone, but it has great potential and may lead to new commercial processes for olefin hydration. (Science 2011, 333, 1609–1612; JosÉ C. Barros)

Make aminoquinazolines from o-amino nitriles in a one-pot, three-step reaction sequence. T. Storz and colleagues at Pfizer (Groton, CT, and Pearl River, NY) synthesized quinazolines and heteroaromatic pyrimidines in one pot and three steps. An o-amino aromatic or heteroaromatic nitrile (e.g., 1) reacts with an acid chloride in sulfolane to produce amido nitrile 2. This mixture is then treated with PCl5 to generate chloroquinazoline 3 or its heteroaromatic equivalent. Finally, adding ammonia or an amine leads displaces the chloride atom to give the aminoquinazoline 4.

The fully telescoped process produces the amine in 48% yield. Alternatively, using the first two steps to produce the chloro compound generally proceeds in 75–90% yield. (Org. Process Res. Dev. 2011, 15, 918–924; Will Watson)

The inside matters: Tune nanotube assembly and functionalization. B. A. Helms, T. Xu, and colleagues at the University of California, Berkeley; Lawrence Berkeley National Laboratory; and Northwestern University (Evanston, IL) prepared peptidic nanotubes that contain functional groups in their interiors. The peptide nanotubes have potential applications in membrane technology.

The authors modified a cyclic peptide [(L-Lys-D-Ala-L-Leu-D-Ala)2], which forms robust 1-D nanotubes, by incorporating a methyl residue in the interior. The methyl group was introduced by substituting the amino acid sequence with an aromatic peptide unit, and the modified peptide was obtained in 30% yield. The methyl group insertion reduced the i.d. of the cyclic structure from ≈7.6 to 4.7 Å and altered the lateral profile of the nanotube.

Directional assembly in MeCN produced 20–40 nm wide, ≈100–500 nm long nanotube bundles. The assembly can be tuned by varying temperature and concentration. Additional interior functionalization changed the assembly pathway and hindered access to the pore space. The authors extended this reversible organization technique by using poly‍(ethylene glycol)–coated cyclic peptide nanotubes, which may improve processibility. (J. Am. Chem. Soc. 2011, 133, 15296–15299; LaShanda Korley)

Morpholinopyrimidine derivatives are potent inhibitors that modulate the pathways of some lipid kinases. The phosphoinositide-3-kinase (P13K) family of lipid kinases participates in critical biological functions at the cellular level, including cell growth and proliferation, motility, differentiation, and survival. In a variety of human cancers, this signaling pathway is deregulated, and it presents a useful therapeutic target for inhibiting tumor growth.

M. T. Burger, S. Pecchi, and co-workers at the Novartis Institutes for Biomedical Research (Emeryville, CA) previously observed that some compounds based on the morpholinopyrimidine scaffold exhibit in vivo P13K pathway modulation, which is accompanied by varying degrees of tumor growth inhibition. Inhibitors such as 1 show subnanomolar cellular potency against the P13Kα isoform, with IC50 values as low as 0.5 nM in rat models. (IC50 is the concentration required for 50% inhibition.)

The authors now report a study of a series of derivatives that they describe as 2-morpholino-4-substituted-6-heterocyclic pyrimidines. Screening tests showed that structure 2 is optimal, and they developed a four–step, high-yield synthesis of 2.

Commercially available starting materials 3 and 6 are used in parallel synthetic paths. Treating 3 with N-bromosuccinimide (NBS) provides bromination at the 4-position, followed by Suzuki coupling with bis‍(boronate ester) 4 to give boronate intermediate 5; dppf is 1,1’-bis‍(diphenylphosphino)‍ferrocene. Concurrently, 6 is treated with morpholine to selectively displace the chlorine atoms at the 2- and 4-positions and give intermediate 7. A second palladium-catalyzed coupling reaction of 5 with 7 leads to target structure 2.

Evaluation across class 1 P13Ks showed that biochemical activity of 2 is in the 50–300 nm range. Structure 2 has the highest solubility and is the most potent of the candidate compounds in cell-based assays. In vitro assays of 2 across several P13K-deregulated cell lines from ovarian, glioblastoma, breast, and prostate tumors showed pathway modulation and antiproliferative activity consistent with cellular P13K inhibition.

The results from the selective in vitro inhibition of class 1 P13Ks translated to in vivo settings when ovarian carcinoma and glioma were used as two models of P13K–Akt (pAkt)–driven cancers. Orally dosing 2 at 3–100 mg/kg nearly completely inhibited the pAkt pathway, and tracked well with plasma and tumor drug exposure.

The authors observed favorable pharmacokinetic properties for 2 across several mammalian species. The compound also exhibits cellular potency, kinase selectivity, and adequate aqueous solubility and clearance. Based on these findings, 2 has advanced into human testing, and phase II trials are under way. (ACS Med. Chem. Lett. 2011, 2, 774–779; W. Jerry Patterson)

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