Noteworthy Chemistry

December 19, 2011

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Aminate chiral benzylic ethers with chlorosulfonyl isocyanate. Earlier this year, Y. H. Jung and coauthors at Sungkyunkwan University (Suwon, Korea), the University of Ulsan (Korea), and Ewha Womans University (Seoul) reported the use of chlorosulfonyl isocyanate (ClO2SNCO, CSI) as a reagent for organic synthesis (Lee, S. H., et al. Tetrahedron Lett. 2011, 52, 1901–1904). Specifically, they used CSI to introduce a chiral amine group at the benzylic position of the tetralin ring system.

This work led the authors to use CSI in syntheses of bioactive structures that contain the tetralin scaffold. A prominent example is (+)-sertraline (Zoloft), a widely used antidepressant that selectively inhibits the reuptake of human synaptosomal serotonin. They report a method for aminating chiral cyclic ethers with CSI and the use of this transformation in an efficient total synthesis of (+)-sertraline (1).

In the basic CSI reaction, benzyl ethers are converted to the corresponding carbamates under mild conditions with yields as high as 89%. Several examples show excellent regioselectivity and recovery of the products in almost diastereopure form.

The authors’ (+)-sertraline synthesis begins with commercially available 1-naphthol (2), which condenses with 1,2-dichlorobenzene to form the tetralin scaffold in ketone 3. The ketone is diastereoselectively reduced to chiral alcohol 5 by using a borane reductant and oxazaborolidine catalyst 4. Subsequent benzylation of 4 gives benzyl ether 6, a key substrate for the reaction with CSI.

This reaction first forms an N-chlorosulfonyl intermediate, which is reduced with sulfite to the desired carbamate 7. Methylating 7 with MeI provides 8 in near-quantitative yield. The carbobenzoxy group is hydrolyzed to generate target structure 1 as its hydrochloride salt.

The authors believe that their CSI-based method will be useful for preparing bioactive structures that contain amine-functionalized tetralin, indane, and cyclic amine scaffolds. (J. Org. Chem. 2011, 76, 10011–10019; W. Jerry Patterson)


Make self-healing actin networks with induced sol–gel transitions. Y. Osada and colleagues at the RIKEN Advanced Science Institute (Saitama, Japan), the Nippon Institute of Technology (Saitama), the Japan Atomic Energy Agency (Ibaraki), and Hokkaido University (Japan) prepared hierarchically organized filamentous actin (F-actin) networks. Actin is an important cytoskeletal protein that is primarily responsible for maintaining the integrity and motility of eukaryotic cells.

The authors covalently cross-linked poly(ethylene glycol) (PEG)–globular actin (G-actin) (a mixture of 2 mol% monofunctional PEG–G-actin, 10 mol% difunctional PEG–G-actin, and 88 mol% untreated G-actin) with NaCl for 1.5 h. They used oscillatory rheological experiments to confirm the formation of a transparent 3-D gel with high storage modulus (G’) values. They believe that the high G’ values are the result of the ordered structural arrangement of the actin filaments. They induced a reversible sol–gel transition by changing the ionic strength of the solution or by applying shear forces. Both actions cause the F-actin gel to depolymerize to G-actin fragments.

The F-actin networks are also self-repairing, as evidenced by the instantaneous recovery of G’ after removing the shear strain. The degree and duration of the strain influence the magnitude and recovery time of G’ in the sol and gel states. Unexpectedly, the recovery of G’ is faster for aged F-actin gels compared with freshly prepared gels; this is most likely because of nucleation effects from the actin fragments. The sol fragments do not denature after oscillatory shear strain.

These results may be useful for probing the formation and structure of actin and its influence on cell behavior. (Biomacromolecules 2012, 12, Article ASAP DOI: 10.1021/bm2009922; LaShanda Korley)


Use an iPad to demonstrate optical activity. Optical activity is characteristic of asymmetric substances and is an important subject in general and organic chemistry courses. A demonstration of optical activity requires a source of polarized light, which is produced by a filter that transmits a single plane of light.

P. M. Schwartz and co-workers at the University of New Haven (West Haven, CT) used an iPad as the source of polarized light to study NaClO3 crystals. (An iPhone or any tablet that can run the Flashlight app can also be used.) The experiment is visualized best in a dark room.

To observe optical activity, the authors placed NaClO3 and NaCl crystals between the iPad screen and a polarized lens (Figure A). When they rotated the lens, they could distinguish the non–optically active NaCl crystal (Figure B, top) from the two optically active forms of NaClO3 (bottom).

Optical activity can also be demonstrated with a glass vessel that contains an aqueous solution of D-sucrose. Any other chiral solute that does not racemize in solution would work as well. (J. Chem. Ed. 2011, 88, 1682–1693, JosÉ C. Barros)


Run a “borrowing hydrogen” reaction on a multikilogram scale. Alkylating an amine with an alcohol under “borrowing hydrogen” conditions is a redox-neutral process in which the catalyst acts as a hydrogen shuttle between the starting alcohol and the secondary amine product. The only byproduct of the reaction is water, which makes the reaction attractive for the chemical industry.

M. A. Berliner and co-workers at Pfizer Global Research and Development (Groton, CT, and Sandwich, UK) report the alkylation of 3-chloro-4-fluorobenzylamine with (3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)methanol—the first published example of the borrowing hydrogen reaction on a multikilogram scale. Two keys to a successful scale-up are adding 2–3% water to keep the reaction from stalling, and running the reaction in a sealed vessel.

Catalyst [(Cp*IrCl2)2] loadings can be as low as <0.05 mol%. (Cp* is pentamethylcyclopentadienyl.) The authors isolated 4.81kg of the secondary amine dihydrochloride product in 76% yield. (Org. Process Res. Dev. 2011, 15, 1052–1062; Will Watson)


Switch on luminescence by locking molecular rotors in polymer networks and coordination frameworks. Molecular rotors such as tetraphenylethylene (TPE) do not luminesce because the dynamic rotation of their multiple rotary units nonradiatively deactivates their excited states. Two research teams, D. Jiang and coauthors at the National Institute of Natural Science (Okazaki, Japan) and the Japan Science and Technology Agency (Tokyo) and N. B. Shustova, B. D. McCarthy, and M. Dincă* at MIT (Cambridge, MA), developed elegant structural design strategies for turning on TPE luminescence by “knitting” TPE units into conjugated microporous polymers (CMPs) or metal–organic frameworks (MOFs).

Jiang’s team used a tetrabrominated TPE derivative as monomer to prepare an interlocked network (1) in which the TPE units link directly to form a 3-D CMP. Network 1 absorbs and emits in the redder spectral region than monomeric TPE and its linear polymer counterparts, and it exhibits less fluorescence depolarization.

Whereas TPE and its linear polymers are weak emitters with fluorescence quantum yields (ΦFL) as low as 0.20%, 1 emits efficiently—even in solution—with ΦFL as high as 40%. The CMP network evidently suppresses intramolecular rotation, enhances emission efficiency, promotes π-electronic conjugation, and facilitates exciton migration.

The Dincă team used a tetracarboxylated TPE derivative as a ligand to synthesize an MOF (2) by complexing the modified TPE with zinc or cadmium ions. Coordinative immobilization of the functionalized TPE units within the rigid, porous MOF switches on TPE light emission. This unique matrix coordination–induced emission effect is associated with the lengthened fluorescence lifetime caused by restricting the intramolecular rotation of the TPE units in 2. The fluorescence response of 2 is easily tuned by the adsorption of small analytes in the MOF, demonstrating its potential for producing new sensing materials. (J. Am. Chem. Soc. 2011, 133, 17622–17625; Article ASAP DOI: 10.1021/ja209327q; Ben Zhong Tang)


A cobalt catalyst ligand controls hydrovinylation regiochemistry. G. Hilt and coauthors at Philipps University Marburg and the University of Cologne (both in Germany) previously used a cobalt-based catalyst system (catalyst A in the figure) for the 1,4-hydrovinylation of terminal alkenes (1) with butadienes (2) to make branched products such as 3 with regioselectivities as high as 99% (Hilt, G.; du Mesnil, F.-X.; LÜers, S. Angew. Chem., Int. Ed. 2001, 40, 387–389). [The ligand dppe is 1,2-bis(diphenylphosphino)ethane.] They have expanded the hydrovinylation reaction with a second-generation cobalt catalyst that contains the SchmalzPhos ligand (catalyst B) to form linear regioisomers such as 4, also with outstanding yields and regioselectivities.

These complementary catalyst systems selectively form new C–C bonds in products 3 and 4 without any other activating or directing additive. This study covers the hydrovinylation of 2 with a range of terminal alkenes. In most cases (including compounds 5 and 6), the product mixture contains a high ratio of the linear isomer to its branched counterpart.

These methods show that the choice of ligand in the cobalt catalyst complex is the key to the reaction’s unusually high regioselectivity. The authors note, however, that whereas the control of the regioselectivity of terminal alkenes is almost 100%, the regioselectivity of the products from unsymmetrical 1,3-dienes is significantly lower.

The catalyst systems promote 1,4-hydrovinylation under very mild conditions and have a high tolerance for diverse functional groups. Importantly, this technique forms 1,4-dienes without isomerization to conjugated systems. (Org. Lett. 2011, 13, 6236–6239; W. Jerry Patterson)


Construct a molecular matryoshka. Intermetalloid clusters are polyhedral structures in which cages of metal atoms encapsulate other metal atoms. S. Stagmaier and T. F. Fässler at the Technical University of Munich describe the synthesis of a more complex intermetalloid cluster that consists of a central tin atom surrounded by an inner copper cage and an outer tin cage (see figure). Because of its similarity to Russian nesting dolls, they call this structure a “bronze matryoshka”.

Structure 1 is an anion with the empirical formula Cu12Sn2112–. The authors initially synthesized it as its sodium salt by heating a mixture of the elements (Na/Cu/Sn atom ratio 1.00:1.00:3.00) to 850 °C for 24 h. Several binary and ternary air-sensitive crystalline structures were formed; powder X-ray diffraction (XRD) analysis showed that one had the formula Na12Cu12Sn21. In addition, a substance with the formula K12Cu12Sn21 was isolated from the products of heating potassium with a previously prepared Cu–Sn phase at 450 °C.

The authors optimized their synthesis by heating a 12:21 Cu–Sn alloy with stoichiometric amounts of alkali metals at 450 °C. The target compounds were the main products when the alkali metal was potassium, rubidium, or cesium; but using sodium produced little of the desired material.

Single-crystal XRD showed that the sodium and potassium products crystallize in the cubic space group Pnm (No. 224) and that the Cu–Sn clusters adopt a face-centered cubic shape. Electronic structure calculations confirmed that the compounds are saltlike intermetallic phases with [Sn@Cu12@Sn20]12–clusters separated by alkali metal cations. (J. Am. Chem. Soc. 2011, 133, 19758–19768; Michael J. Block)


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