Rational Design and Evaluation of Upgraded Grubbs/Hoveyda Olefin Metathesis Catalysts: Polyfunctional Benzylidene Ethers on the Test Bench

The series of upgraded Grubbs/Hoveyda second-generation catalysts (H2IMes)(Cl)2RuC(H)(C6H4OR) (E2 (71% yield), R = CH(Me)(C(O)OMe); M2 (58% yield), R = CH(C(O)OMe)2; Kme2 (88% yield), R = CH2C(O)Me; Ket2 (63% yield), R = CH2C(O)Et); C2 (58% yield), R = C(Me)CN) were prepared by the reaction of the Grubbs second-generation catalyst (H2IMes)(Cl)2Ru(CHPh)(PCy3) (G2) with the appropriate ortho-substituted ether H(Me)CCHC6H4OR in the presence of CuCl as a phosphine scavenger. The X-ray structures of these complexes reveal that the terminal oxygen of the ester, ketone, or malonate group installed as the terminal substituent of the benzylidene ether is coordinated to the metal, giving an octahedral structure. In contrast, the nitrile group of the complex C2 remains uncoordinated. Even more sophisticated complexes, incorporating both a coordinating group R (ester or ketone) as a terminal substituent of the ether and an electron-withdrawing group X (NO2 or C(O)Me) on the aromatic ring, were synthesized: (H2IMes)(Cl)2RuC(H)[(C6H3X)OR] (NE2 (69% yield), R = CH(Me)(C(O)OMe), X = NO2; KE2 (57% yield), R = CH(Me)(C(O)OMe), X = C(O)Me; KK2 (56% yield), R = CH2C(O)Me, X = C(O)Me). All these complexes were used as catalyst precursors in standard metathesis reactions and compared with commercial catalysts such as Grubbs II (G2), Grubbs/Hoveyda II (H2), and Nitro catalyst (N2). The catalysts NE2, KE2, N2, and M2 exhibit excellent performances in the RCM of diallyl malonate or the RCM of diallyltosylamide at 0 °C. The catalysts M2, N2, and Kme2 are also very efficient for the RCM of allyl methallyl malonate to yield a trisubstituted olefin. The same complexes are also active for cross-metathesis, and several low-loading tests are also presented. Finally, a very challenging example of the synthesis of BILN 2061 (hepatitis C virus HCV NS3 protease inhibitor having antiviral effect in infected humans) is presented, where the best performances are recorded with E2 (95% conversion) and N2 (93% conversion). The enhanced activity of the reported complexes is understood in terms of their enhanced stability and their ability to liberate progressively and continuously the active species in solution.