Noteworthy Chemistry

October 15, 2012

Assemble pentaaryldiazaboroles in one step. First synthesized 40 years ago by J. S. Merriam and K. Niedenzu (J. Organomet. Chem. 1973, 51, C2–C2), 1,3,2-diazaboroles are useful aromatic boracycles because of their unique electronic properties and reactivity. Whereas unsubstituted and 4,5-benzo derivatives (1 and 2, respectively, in the figure) are the most commonly studied diazaboroles, 4,5-aryldiazaboroles (3) are rare because they are difficult to synthesize. C. Cui and co-workers at Nankai University (Tianjin, China) report a way to access pentaaryldiazaboroles (3, R1 = R2 = Ar) from imidoylstannanes in one step.

The authors first prepared imidoylstannanes (e.g., 4) from the corresponding imidazoyl chlorides and Me3SnLi. They then treated 2 equiv 4 with 1 equiv PhBBr2 or MesBBr2 (Mes = 2,4,6-Me3C6H2) in n-hexane to form the desired pentaaryldiazaboroles (e.g., 6) in moderate yields (40−62%). In addition, they obtained bisdiazaborole 8 in 27% yield by treating 4 equiv 7 with 1 equiv Br2BC6H4BBr2. Isolating the donor-acceptor complex 5 supported the proposed mechanism, in which the C=C bond forms via the dimerization of a carbene intermediate, Mes(PhBrB)N(Ph)C:, which is generated by heating 5 to eliminate Me3SnBr.

Crystal structures of selected pentaaryldiazaboroles showed that all aryl substituents except those on boron adopt a twisted geometry with respect to the diazaborole rings. All of the diazaboroles fluoresce in solution (ΦF = 0.06−0.90) and the solid state (ΦF = 0.01−0.40). (J. Am. Chem. Soc. 2012, 134, 14666–14669; Xin Su)

Cooling rate influences particle morphology. Using a programmed heating and cooling cycle, Z.-m. Li, X.-l. Luo, and collaborators at Sichuan University (Chengdu, China) developed a method to synthesize nanocubes from dilute solutions of linear or star poly(ε–caprolactone) (LPCL or SPCL) . Smooth, symmetric nanocubes (≈78 nm edge length) consisting of flat-on PCL lamellae are obtained from LPCL and SPCL; however, the quantity of nanocubes obtained from SPCL is greater than obtained from LPCL.

The choice of substrate has a significant effect on whether nanocubes are formed. The authors observed that the cooling step after thermal evaporation has a profound effect on shape evolution. Slow cooling produces nanocubes, whereas thermally quenching the evaporated PCL film yields droplets. (ACS Macro Letters 2012, 1, 933–936; LaShanda Korley)

Modulate the light emission from a luminogenic terminus by modifying the main and side chains of vinyl polymers. Many luminogenic molecules with aggregation-induced emission (AIE) characteristics have been synthesized, but few examples of polymers with AIE are known. Large polymers are preferable to small molecules for use in electronic devices because of their macroscopic processibility.

In addition to giving polymers AIE activity, integrating AIE units into polymer chains may allow sensitive probing into their morphologies and properties. Q.-F. Xu, J.-M. Lu, and co-workers at Soochow University (Suzhou, China) introduced a single AIE unit into a polymer chain with an elegantly designed AIE initiator (1) for atom-transfer radical polymerization (ATRP).

The researchers synthesized a series of AIE-terminated vinyl polymers with different polarities by initiating ATRP with 1. They achieved the greatest AIE effect (155-fold emission enhancement) in polystyrene, which was the most hydrophobic and highest molecular weight polymer they produced. The authors attribute the large AIE effect to the hydrophobic and wrapping effects of the long polymer chain on intramolecular charge transfer and intramolecular rotation of 1.

The AIE effect gradually weakens with increasing polarity in the side chains of vinyl polymers in the order polystyrene → poly(methyl methacrylate) → poly(2-hydroxyethyl methacrylate) (PHEMA). The emission of 1-terminated PHEMA is enhanced by increasing pH, which allows the AIE polymer to serve as a fluorescent pH probe in simulated gastric juice. (Chem. Commun. 2012, 48, 10234–10236; Ben Zhong Tang)

A thiophene–sulfone molecule inhibits cancer-related enzymes. Ubiquitin is a key protein for mediating cell proliferation. The ubiquitin system is regulated by a series of enzymes called deubiquitylating enzymes. Some of these enzymes, such as USP7 and USP47, are closely associated with cancer. Inhibiting USP7 increases the levels of the tumor suppressor protein p53 and makes the enzyme a good target for cancer treatment.

To identify new inhibitors for USP7 and USP47, B. Nicholson and co-workers at Progenra (Malvern, PA) began by screening commercial libraries for USP7 inhibitors. After several successive screenings, they narrowed the field to compound 1.

The authors then optimized the solubility and potency of 1. They first focused on substituents on the thiol at position 5 of the thiophene and found that the greatest improvement over 1 was structure 2. They next turned their attention to substituents directly on the thiophene moiety. Optimization led to compound 3, which had increased stability, solubility, and potency for inhibiting USP7 and USP47. The authors attribute the increased stability to replacing the nitro group at position 4 with nitrile.

In vitro tests of 3 on cancer cells showed an increase in p53 concentration, confirming its inhibition of USP7. Compounds with dual inhibition properties such as 3 reduce susceptibility to drug resistance and merit further investigation in cancer treatment. (ACS Med. Chem. Lett. 2012, 3, Article ASAP DOI:10.1021/ml200276j; Chaya Pooput)

Which is the best keto ester to convert to a hydroxy amide? Two steps in the synthesis of an H3 antagonist involve adding an organomagnesium “ate” complex to a derivative of cyclobutanone-3-carboxylic acid followed by converting the product to the corresponding ethylamide. J. M. Hawkins and co-workers at Pfizer (Groton, CT) found that starting with the cyclobutanone ethylamide or the carboxylic acid magnesium salt was unsuitable because of low yields.

The methyl ester gave higher yields, but it led to overreaction with the magnesium ate species. Using the isopropyl ester significantly reduced the levels of overreaction side products. A MeOH quench of the Grignard reaction mixture transesterified the isopropyl ester to the methyl ester. This allowed EtNH2 to be added for forming the amide.

The authors believe that the neighboring alkoxide group assists in the transesterification, possibly through a strained lactone intermediate. (Org. Process Res. Dev. 2012, 16, 1398–1403; Will Watson)

The iodoform reaction inspires a synthesis of α-keto amides. α-Keto amides are useful intermediates for synthesizing natural products and biologically active compounds. X. Wan and coauthors at Soochow University (Suzhou), Changzhou University, and Huaiyin Normal University (Huaian, all in China) were inspired by the iodoform reaction to develop a preparation of α-keto amides. In the iodoform reaction, which dates to 1822, methyl ketones are iodinated three times then treated with hydroxide to make carboxylic acids after iodoform (CHI3) precipitates.

The authors’ method uses a catalytic amount of an iodine compound (50 mol% to ensure monoiodination), amines as nucleophiles to displace iodide, and an oxidant to produce α-keto amides by C–H bond oxidation. Optimizing the reaction conditions showed that molecular iodine, morpholine, and t-BuOOH were the best iodinating combination.

Several substituted aromatic or heteroaromatic methyl ketones were suitable substrates, along with some cyclic or acyclic, primary or secondary amines. A scaled-up reaction (100 mmol) between acetophenone and morpholine gave an 82% yield. This method is an alternative to α-keto amide production that does not require a transition-metal catalyst for the C–H bond oxidation (J. Org. Chem. 2012, 77, 7157–7165; JosÉ C. Barros)

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