Chemistry

Arene Choreography

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Science  03 Apr 2009:
Vol. 324, Issue 5923, pp. 15
DOI: 10.1126/science.324.5923.15b

Selective substitution of benzene derivatives is a key component of pharmaceutical and fine chemicals synthesis. In general, the easiest positions to modify are the ring carbons directly adjacent to or across from electron-rich substituents already present. Electron-withdrawing groups, in contrast, tend to reduce inherent reactivity toward further substitution, thus hampering direct synthetic strategies for a wide range of desirable products. Zhang et al. have addressed this challenge through careful ligand design in palladium-catalyzed addition (via C-H activation) of unsaturated esters to electron-poor arenes to yield olefin-substituted products. The optimal, pyridine-based ligand was sufficiently electron-rich to facilitate reoxidation of the metal after an addition cycle, but also strategically bulky so as to hinder coordination of a second such ligand after the first had bound, thereby leaving a site open for the weakly coordinating arene substrate. The catalyst selectively appended acrylate and cinnamate derivatives at the meta position (two carbons away) of nitro-, trifluoromethyl-, and ester-substituted arenes. More conventional, directed palladium-catalyzed addition facilitated further substitution at the ring carbons in between. The method complements a recently reported meta-selective arylation employing a copper catalyst (see Phipps and Gaunt, Reports, 20 March 2009, p. 1593). — JSY

J. Am. Chem. Soc. 131, 10.1021/ja900327e (2009).

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