Noteworthy Chemistry

March 28, 2011

A catalytic domino reaction provides easy access to ampakines. A promising therapy for devastating neurodegenerative diseases such as Alzheimer’s and Parkinson’s uses drugs based on the ampakine scaffold (1). One useful class of compounds is 3-substituted 1,2,3-benzotriazinones (2). Derivatives of 2 have the potential for treating neurodegenerative disorders via positive allosteric modulation of AMPA receptors at concentrations in the nanomole range. (AMPA is α-amino-3-hydroxy-5-methyl-4-isoxazole propionate.)

M. Mulzer and G. W. Coates* at Cornell University (Ithaca, NY) recognized the value of an efficient synthesis of the ampakine framework. They report a synthesis based on hydroformylating simple dihydrooxazines.

The cobalt-mediated hydroformylation of dihydrooxazine 3 results in a domino process that culminates with cyclization to give compound 4 in yields as high as 81%. Such easy access to this structure is of interest because the effects of 4 on cell receptors are well documented.

The reaction scales up efficiently, with essentially no loss in isolated yield. Substituents on the phenyl and oxazine rings produce a range of structural variants, which suggests routes to pharmaceutically valuable compounds. As an example, structure 5 with a key methyl substituent provides an important building block for synthesizing 2. (Org. Lett. 2011, 13, 1426–1428; W. Jerry Patterson)


A surprise is encountered during an impurity synthesis. Fulvestrant, a steroidal antiestrogen targeted toward breast cancers, is prepared via a 1,6-addition of an organocuprate to a steroidal dienone to introduce the CF3CF2(CH2)3S(CH2)9 side chain. One fulvestrant impurity arises from addition at both ends of 1,9-dibromononane (an impurity in the side-chain starting material) to give a “sterol dimer”. Attempts to prepare this impurity directly from 1,9-dibromononane by cuprate addition using the same conditions as in the Fulvestrant synthesis were unsuccessful.

A literature review by L. Powell*, A. Mahmood, and G. E. Robinson at AstraZeneca (Macclesfield, UK) and observation of the structure of the side chain suggested that sulfur might be stabilizing the cuprate intermediate. Adding Me2S and changing the order of addition gave a 75% yield of the desired “dimer”. (Org. Process Res. Dev. 2011, 15, 49–52; Will Watson)


Use a paper support to screen antibacterial chalcones. There is an urgent need for new antibacterial agents against methicillin-resistant Staphylococcus aureus (MRSA), which is increasingly prevalent in hospitals and other settings. One way of discovering efficacious compounds is to screen combinatorial libraries of small molecules.

H. E. Blackwell and co-workers at the University of Wisconsin (Madison) used paper as a microarray support for the parallel synthesis of a chalcone library and tested the compounds against MRSA. They modified a cellulose support (filter paper) by substituting hydroxyl groups with amino groups. They also introduced a spacer called a Rink amide linker. They treated the amino support (1) with acetylphenoxyacetic acids by using the standard peptide coupling reagent N,N’-diisopropylcarbodiimide (DIC). The Claisen–Schmidt reaction of coupled products 2 with benzaldehydes produced supported chalcones 3. Finally, each spot was removed from the solid support and subjected to CF3CO2H vapor to obtain free chalcones 4.

The authors prepared 174 chalcones with this method. The compounds were 72–99% pure as measured by HPLC, and the amount of each chalcone was ~113 nmol/spot. Three of the chalcones were active against MRSA, with minimum inhibitory concentrations comparable to linezolid. (ACS Comb. Sci. 2011, 13, 175–180, JosÉ C. Barros)


Recover bitumen with poly(N-isopropylacrylamide). Bitumen is a viscous crude oil that coexists with sand, clay, and water in oil sands. The technology for recovering bitumen has improved greatly, and investment in processing oil sands has increased correspondingly. Improving bitumen extraction efficiency is a major goal and has attracted much research activity.

Polymers, mostly hydrolyzed polyacrylamides, have been used to assist bitumen recovery. However these polymers do not efficiently separate bitumen from solids. J. Long, Z. Xu*, and J. H. Masliyag at the University of Alberta (Edmonton) used an alternative polymer, poly(N-isopropylacrylamide) (PNIPAM, 1), as an additive for processing oil sands in an attempt to improve bitumen recovery.

PNIPAM is temperature-responsive and undergoes a phase transition at ~30 °C. At ambient temperature, intermolecular hydrogen bonds form between water molecules and the amide groups on the polymer side chains. This hydrolyzed moiety cannot interact with oily compounds and hinders bitumen recovery. At 40 °C, however, the intermolecular forces are disrupted, and the polymer is freed. The bitumen recovery rate increases dramatically, and the oil yield doubles. The polymer also flocculates moderate amounts of solid particles. Sand and clay are efficiently separated from the liquid in less time than with control treatments. (Energy Fuels 2011, 25, 701–707; Sally Peng Li)


Spin fibers from natural cellulose nanofibers. S. Iwamoto, A. Isogai, and T. Iwata* at the University of Tokyo prepared fibers consisting of cellulose nanofibers derived from oxidized wood (~3.2 nm diam, 200–500 nm long) and tunicate cellulose (~8.4 nm thick, ~20.3 nm wide) via wet-spinning. (A tunicate is a sea animal.) The nanofibers produced from wood cellulose at all spinning rates had smooth surfaces, but higher spinning rates (>10 m/min) created cross-sections with hollow internal structures.

Compared with bulk films, the wood-based cellulose fibers are highly aligned along the fiber axis; the alignment increases with spinning rate. This orientation contributes to an increase in tensile strength and longitudinal Young’s modulus. In contrast, the tunicate-based cellulose nanofibers produce fibers with pronounced surface roughness and an isotropic surface arrangement of nanofibers, exhibit porous nanofiber structure, and maintain cylindrical fiber morphology because of their higher solution viscosity.

Similarly, X-ray diffraction studies showed alignment of the tunicate-derived nanofibers along the fiber axis; sheetlike nanostructures appeared in the porous internal region. Fibers made from tunicate are tougher than those derived from wood, primarily because of a filler aspect ratio effect. (Biomacromolecules 2011, 12, 831–836; LaShanda Korley)


Selectively isomerize propargylic alcohols to (E)-enones. The usefulness of the trifluoromethyl group for enhancing the bioactivity of molecules is well established, as illustrated by its incorporation into many important drug structures. Earlier work showed that propargylic alcohols with a trifluoromethyl group at the distal position of the triple bond can readily be converted to enones (Yamazaki, T., et al. Tetrahedron 2009, 65, 5945–5948).

Y. Watanabe and T. Yamazaki* at Tokyo University of Agriculture and Technology (Koganei, Japan) now report the first example of redox isomerization of trifluoromethyl-substituted propargylic alcohols (e.g., 1) to (E)-α,β-enones (e.g., 2) by treating them with Mitsunobu reagents. [TMPP is tris(p-methoxyphenyl)phosphine; ADDP is 1,1’-(azodicarbonyl)dipiperidine.]

Their method proceeds without transition-metal catalysts, which is an important “green” consideration. It also works well with alkyl or aryl substituents on the trifluoromethylpropargyl alcohol—an advantage missing in earlier synthesis methods. (E)-Isomer 2 is formed exclusively in almost all cases, and yields are as high as 98%.

In an earlier phase of their study, the use of PPh3 as the phosphine component yielded a Z/E ratio of 3:1. The authors performed an isomerization experiment and demonstrated that TMPP promotes almost perfect conversion of (Z)-isomer 3 to (E)-isomer 4 (Z/E = 1:99). This verifies that the presence of TMPP efficiently drives any equilibrium of isomeric products to the (E)-isomer.

The authors’ method features a highly efficient synthesis of trifluoromethyl-substituted enones with extremely high (E)-selectivity. It uses mild conditions and eliminates the need for transition-metal catalysts. (J. Org. Chem. 2011, 76, 1957–1960; W. Jerry Patterson)


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