February 1, 2010
Direct arylations of indazoles can be performed “on water”. The concept of direct arylation for synthesizing arylindazoles is a useful alternative to the more conventional cross-coupling methods. The indazole scaffold has significant potential in medicinal chemistry and is particularly important in kinase inhibition. This concept has the advantage of direct arylation at the C3 position, and it significantly simplifies the synthesis of aryl-substituted indazole structures.
M. F. Greaney and coauthors at the University of Edinburgh and the Novartis Horsham Research Center (both in the UK) developed an “on-water” direct arylation technique in which the substrate and catalyst form a heterogeneous mixture in pure water. The reaction is mediated by a palladium–diphenylphosphinoferrocene (dppf) catalyst with an additional PPh3 ligand and a silver salt under mild conditions.
A typical on-water reaction between 2-phenylindazole (1) and a variety of aryl halides as the reactants proceeds cleanly to form the desired product (2) in high yields. The process is usually effective for aryl iodides and bromides; and it tolerates functional groups such as halides, methoxy, nitrile, acyl, and the N-protecting group 2-(trimethylsilyl)ethoxymethyl.
The on-water reaction is straightforward and allows easy product purification. The authors note that this is the first report of intermolecular direct arylation of indazoles. (Org. Lett. 2010, 12, 224–226; W. Jerry Patterson) [A similar method for the direct arylation, alkenylation, and benzylation of oxazoles was recently reported in Organic Letters.—Ed.]
Unique surface folding patterns occur in ultrathin hydrogel films attached to a substrate. S. Singamaneni, M. E. McConney, and V. V. Tsukruk* at Georgia Tech (Atlanta) describe the buckling behavior of ultrathin (20–100 nm) poly(2-vinylpyridine) (P2VP) hydrogel films confined to a silicon substrate. The P2VP surface is smooth at pH 4; but the film changes to a nonuniform, folded (~30°) surface morphology when acidified to pH 2. This thickness-dependent buckling phenomenon yields hinge domains with one straight side and limb domains with one or two vertices.
A height profile of the buckled films shows a trimodal distribution that corresponds to single (~140 nm) and double (~270 nm) folds in addition to the the stretched adhered layer (22 nm). When thin hydrogels adhering to a rigid substrate are swollen, nodes form because of the interaction of pinched buckles and lead to lenticular structures. Drying the swollen P2VP films induces the growth of the folded domains. As the stretched regions approach a critical thickness (~20 nm), fold growth is limited. No surface-folding behavior occurs with stiffer hydrogel ultrathin films with limited swelling capacity.
Using patterned arrays as internal strain monitors, the researchers determined that the folding process causes 100% strain and that the deformation mode is predominantly in-plane shearing. The aspect ratio (~5:1) of the folded structures remains remarkably constant for the range of film thicknesses (23–90 nm) investigated; this is attributed to mechanics-regulated folding. (Adv. Mater. 2010, 22, Early View DOI: 10.1002/adma.200903052; LaShanda Korley)
How do molecules pack in gels? Gels have been studied extensively, but little is known about molecular packing in the gels because their imperfect order prevents the use of powerful techniques such as X-ray diffraction (XRD) crystallography. J. Cui, Z. Shen*, and X. Wan* of Peking University (Beijing) synthesized a novel gelator, 4-(4’-ethoxyphenyl)phenyl-β-O-D-glucoside (1), and found that it undergoes a gel-to-crystal phase transition in 1:4 v/v 1,4-dioxane–H2O.
The researchers used several analytical techniques, including XRD, to study the gel-to-crystal transition. In addition to determining the nature of the structural change during the phase transition, the data produced useful information about the packing arrangement in the gel phase.
In the gel phase, the molecules of 1 form bilayers with overlapping ethoxy tails. Driven by surface tension, the molecular sheets glide into each other, and the gel collapses. When the tails move to a position that allows hydrogen bonding between the ethoxy and glycosyl groups, intermolecular edge-to-face CH–π interactions occur and culminate in crystal formation. (Langmuir 2010, 26, 97–103; Ben Zhong Tang)
Watch out for impurities formed during drying. D. E. Patterson and co-workers at GlaxoSmithKline (Research Triangle Park, NC) describe a large-scale synthesis of denagliptin p-toluenesulfonate, a diabetes drug under development. The final step in the synthesis is to remove an N-tert-butoxycarbonyl protecting group with p-toluenesulfonic acid (TsOH) in i-PrOH. The authors found varying amounts of three impurities in the isolated product after drying, all of which result from the degradation of the compound’s nitrile group to the amide, carboxylic acid, or isopropoxyimidate.
The impurities are not generated during the reaction but form during the drying step when excess TsOH is present in the drying cake. Washing the cake twice before drying removes excess TsOH and avoids the formation of impurities. (Org. Process Res. Dev. 2009, 13, 900–906; Will Watson)
Here’s a new way to demonstrate SN1 reactions. The unimolecular substitution reaction (SN1) is one of the most fundamental transformations in organic chemistry. When this reaction is used to instruct students about mechanisms and isolation and characterization techniques, the conversion of tert-amyl alcohol to tert-amyl chloride is often chosen as a model. In this case, the workup procedure involves separatory funnel extraction, drying over an adsorbent, and evaporating the solvent.
C. F. Wagner* and P. A. Marshall at Arizona State University at the West Campus (Glendale) developed a safe, economical, and effective SN1 experiment that uses 2,5-dimethyl-2,5-hexanediol (1) and concd HCl as starting materials.
In the first part of the experiment, 2,5-dichloro-2,5-dimethylhexane (2) is prepared by the SN1 reaction. HCl is added to 1 with gentle swirling, the solid dissolves, and a white precipitate with a different texture from the starting material forms. The precipitate is filtered with a Büchner funnel and washed with water.
In the second part, students test the solubility of 1 and 2 in MeOH, EtOAc, and hexane to familiarize themselves with the concept of polar protic, polar aprotic, and nonpolar solvents. The third part is thin-layer chromatography of reagent and product and focuses on teaching concepts such as reaction monitoring, eluent polarity, and stains (e.g., phosphomolybdic acid used here). The product is characterized by using Fourier transform (FT) IR or NMR.
The authors include hazardous material instruction and student learning assessments for this experiment. They give FTIR, 13C NMR, and 1H NMR spectra of the starting material and product in the supporting information. This method is an improvement over traditional undergraduate laboratory practices for SN1 experiments with its simple workup procedure and readily available starting materials. (J. Chem. Ed. 2010, 87, 81–83; José C. Barros)
Use phage-displayed peptides for recognition of patterned molecular inks. M. C. McAlpine* and colleagues at Princeton University (NJ) used a phage-displayed peptide screen processing to identify specific peptide–molecular ink (octyltrimethoxysilane, or C8) binding and to fashion patterned arrays based on this targeted binding. The robust screening protocol sampled a C8-coated silicon substrate to identify C8-selective phage-displayed peptide (SILPYPY). SILPYPY recognition of the C8-functionalized surface was supported by high fluorescence intensity compared with an unfunctionalized silicon substrate or C8-coated silicon exposed to nonselective phages or peptide sequences without phage displays.
The authors used microcontact printing and photolithography techniques to pattern the silicon surface (5 μm line width with 10 μm center-to-center spacing) with C8 ink. They show that the ink-patterned regions have fluorescence intensities characteristic of phase-displayed peptide binding between C8 and SILPYPY. This work shows promise for generating multiple recognition schemes suitable for a host of biotechnology applications. (J. Am. Chem. Soc. 2010, 132, 1204–1205; LaShanda Korley)
Form substituted naphthalenes efficiently via aminobenzannulation without using metallic catalysts. A variety of benzannulation strategies have been developed over the years; they typically use expensive metallic catalysts that contribute to the complexity of the synthesis. T. Jin, Y. Yamamoto, and co-workers at Tohoku University (Sendai, Japan) report an alternative approach: metal catalyst–free benzannulation of 2-(2-propynyl)(oxo)benzenes (e.g., 1) with dialkylamines that yields a variety of substituted naphthalenes. A notable feature of their method is that the desired products can be formed at room temperature in many cases, promoted only by molecular sieves.
The product of the reaction shown is a 2-aminonaphthalene (2), an important scaffold in medicinal chemistry with a wide range of applications. The authors’ study encompasses efficient reactions of acyclic and cyclic dialkylamines. Several cyclic amines require temperatures up to 100 °C for efficient conversions. The authors extended the study to naphthalene-containing substrates to form 3-aminophenanthrenes under the same reaction conditions.
Oddly, when the substrates are acetophenone structures, without substituents or with an electron-donating group on the phenyl ring, the reaction with Et2NH gives 1-aminonaphthalenes rather than the expected 2-substituted products. The authors do not give an explanation for this anomalous behavior. (Org. Lett. 2010, 12, 388–390; W. Jerry Patterson)
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