Noteworthy Chemistry

July 9, 2012

Water is an excellent solvent for imidazole carbonylation. Urea and carbamate are important structures in organic synthesis and medicinal chemistry. Introducing these structures usually requires toxic compounds such as phosgene or isocyanates as the carbonyl group source. Another source of carbonyls is the much milder 1,1’-carbonyldiimidazole (CDI, 1); it reacts with water to liberate CO2 and with amines in organic solvents to displace one imidazole group and produce carbonylimidazolides (2).

K. J. Padiya and co-workers at Nycomed Pharma (Mumbai, India) report the reaction of CDI with amines in water at 0 °C. They used primary (illustrated), secondary, linear, cyclic, or aromatic amines as substrates. The reactivity of the amines decreases as nucleophilicity increases. Because water is present, the carbonylimidazolide product usually precipitates from the reaction mixture. Although CDI is unstable in water, its reaction with amines is so rapid that the reaction proceeds with good yields.

Reactions of carbonylimidazolides with a different amine, the original amine, a phenol, or a thiophenol, generate an asymmetric urea (3), a symmetric urea (4), a carbamate (5), or a thiocarbamate (6), respectively. Because carbonylimidazolides are less reactive than CDI, however, the reactions must be performed at room temperature; some carbonylimidazolides are so stable that they do not react.

Both reactions can be performed in one pot. The authors screened several solvents and found that water is best. Hydrogen bonding with water makes the CDI carbonyl group highly electrophilic, and amines are more nucleophilic in water than in organic solvents. This study represents a paradigm shift because the instability of CDI in water is used as an advantage. (Org. Lett. 2012, 14, 2814–2817; JosÉ C. Barros)

A series of screenings yields potential HIV inhibitors. The HIV-1 nucleocapsid is a small protein encoded within the Gag polyprotein. In mature, infectious virus particles, the nucleocapsid forms a complex with HIV genomic RNA and plays a crucial role in reverse transcription. Disrupting the nucleocapsid–RNA interaction would impair the infectivity of the virus and make the nucleocapsid a potential antiviral target.

B. E. Torbett and co-workers at the Scripps Research Institute (La Jolla, CA) set out to identify new compounds that would interfere directly with the nucleocapsid–RNA complex. In the first of two screenings, they used fluorescence polarization assays on a library of 14,400 small molecules to identify 101 compounds that disrupt the nucleocapsid–RNA interaction. In the second screening, they measured the thermal stability of the nucleocapsid–test compound complexes by using differential scanning fluorimetry; 36 of the 101 compounds satisfied the thermal stability criterion of the screen.

Of these 36, the authors selected only 18 because they inhibit the nucleocapsid–RNA interaction by >60%. They then performed enzymatic assays, which identified eight to be “promiscuous” inhibitors, and they eliminated them from further consideration. Another set of evaluations ruled out five more molecules for promiscuous binding. The remaining five compounds were tested for cellular toxicity and anti–HIV-1 activity. Only compounds 1 and 2 have low toxicity and modest antiviral activity.

Even though these molecules have lower activity than desired, they may provide structural insight for designing more efficient antiviral agents. Moreover, the authors developed a relatively easy-to-use high-throughput screening process that would accommodate a larger and more diverse chemical library for identifying compounds with higher antiviral activity. (J. Med. Chem. 2012, 55, 4968–4977; Chaya Pooput)

Force a Diels–Alder reaction to completion. In the synthesis of a potential schizophrenia drug, the reductive amination of a furfuraldehyde with 4-trifluoromethoxybenzylamine produces a secondary amine that can be converted to an isoindolone in a three-step, one-pot process. Treating the amine with crotonyl chloride gives an amide that, after a water wash, is heated at reflux in toluene to form a tricyclic Diels–Alder adduct. A competing retro-Diels–Alder reaction, however, holds the amide conversion to ≈75%.

M. Golden and coauthors at AstraZeneca (Macclesfield, UK) and Torcan Chemical (Aurora, ON) improved the final step by adding MeSO3H under Dean–Stark conditions. This modification forces the equilibrium of the Diels–Alder reaction toward complete consumption of the amide. The overall yield from the three-step process is 70%. (Org. Process Res. Dev. 2012, 16, 741–747; Will Watson)

“Bridge” the nucleophilicity–electrophilicity gap in an N-heterocyclic carbene. Classical N-heterocyclic carbenes (NHCs) are widely used as nucleophiles and σ-donor ligands. Modifications to enhance their electrophilicity, however, often sacrifice nucleophilicity. G. Bertrand and co-workers at the University of California, Riverside, developed a strategy to enhance the electrophilicity of NHCs without impairing the nucleophilicity by placing one nitrogen atom at a bicyclic bridgehead.

Computational predictions showed that the pyrimidalized bridgehead nitrogen effectively lowers the energy of the lowest unoccupied molecular orbital and leaves the energy of the highest occupied molecular orbital unchanged. The bridgehead nitrogen becomes σ-withdrawing, but the other nitrogen remains π-donating.

Based on these results, the authors synthesized amidinium 3 in 70% yield from 3-piperidinemethanol (1) by condensing it with ethyl N-2,6-diisopropylphenylformamidinate (2) and cyclizing in the presence of (CF3CO)2O. Amidinium 3 is then deprotonated by potassium hexamethyldisilazide (KHMDS) at –78 °C to give NHC 4 in 62% yield.

The NHC is stable in solution and the solid phase at room temperature. The 13C NMR signal of the carbene center in 4 is shifted downfield relative to that of monocyclic diaminocarbenes, and it is close to that of other electrophilic NHCs. The crystal structure of 4 exhibits a pyrimidalized bridgehead nitrogen with an elongated N–carbene center bond.

As a strong nucleophile, 4 instantaneously reacts with CO2 to quantitatively form the corresponding betaine adduct. The authors estimate that the basicity of 4 is similar to the classical NHC 1,3-bis(2,6-diisopropylphenyl)imidazolidin-2-ylidene (5). Iridium complex 6 formed from 4 shows significant π-accepting character but retains its σ-donating character. Treating 4 with cyclohexyl isocyanide produces keteneimine coupling product 7, which has not been observed with classical NHCs. (Angew. Chem., Int. Ed. 2012, 51, 6172–6175; Xin Su)

Optical “sniffer” detects plasticizers in plastic explosives with great differentiating power. Plastic explosives, such as Semtex and C4, have become popular with terrorists. They are called “plastic” because plasticizers occupy a large portion of the explosive mixtures. Although much effort has been devoted to assaying pure explosives in the laboratory, detecting explosives in mixtures has been investigated far less. Explosive mixtures contaminated by solids, which is often the case in real-life assays, remain virtually unexplored.

E. V. Anslyn and coworkers at the University of Texas at Austin used cross-reactive serum albumin protein to detect and differentiate plasticizers in explosive mixtures. Their sensing ensemble consists of serum albumins, fluorescent indicators, and an additive.

The authors classified the plasticizers shown in the figure by using linear discriminate analysis, and they differentiated simulated Semtex and C4 mixtures and their plasticizer compositions. They demonstrated the utility of differential arrays for use in a battlefield setting by examining the explosive mixtures in the presence of soil contaminants. (Chem. Sci. 2012, 3, 1773–1779; Ben Zhong Tang)

What do you think of Noteworthy Chemistry? Let us know.