Molybdenum chloride catalysts for Z-selective olefin metathesis reactions

Abstract

Development of catalyst-controlled stereoselective olefin metathesis processes1 has been a pivotal recent advance in chemistry. Incorporation of appropriate ligands within molybdenum-2, tungsten3 and ruthenium-based complexes4 has made reactivity and selectivity levels that were formerly inaccessible feasible. Here, we show that molybdenum monoaryloxide chloride (MAC) complexes furnish higher energy (Z) isomers of trifluoromethyl-substituted alkenes through cross-metathesis (CM) reactions with commercially available, inexpensive and typically inert Z-1,1,1,4,4,4-hexafluoro-2-butene. Furthermore, otherwise inefficient and non-stereoselective transformations with Z-1,2-dichloro- and 1,2- dibromoethene can be effected with substantially improved efficiency and Z selectivity. Synthesis of representative biologically active molecules and trifluoromethyl analogues of medicinally relevant compounds underscore the importance of the advance. The origins of activity and selectivity levels, which contradict the previously proposed principles5, are elucidated with the aid of DFT calculations.

Synthesis of E- and Z-trisubstituted alkenes by catalytic cross-metathesis

“…I - II , Fig. 2c), use of monoaryloxide chloride species Mo-4 37 led to improved efficiency; for example, Z - 18 was isolated in 28% yield when pyrrolide complex Mo-3 was used (compared to 64% yield). Mo chloride complexes are ineffective in promoting reactions that afford alkenyl halides, as decomposition of the purported chloro- or bromo-substituted metallacyclobutanes is probably facile 37 .…”

“…2c), use of monoaryloxide chloride species Mo-4 37 led to improved efficiency; for example, Z - 18 was isolated in 28% yield when pyrrolide complex Mo-3 was used (compared to 64% yield). Mo chloride complexes are ineffective in promoting reactions that afford alkenyl halides, as decomposition of the purported chloro- or bromo-substituted metallacyclobutanes is probably facile 37 . The present approach complements a recent study regarding stereoselective synthesis of trisubstituted alkenes starting from carboxylic acids and involving alkenylzinc reagents, which are often derived from alkenyl halide precursors 38 .…”

Stereoretentive Olefin Metathesis: An Avenue to Kinetic Selectivity

“…[86] Studies aimed at better understanding the catalytic intermediates during these transformations led to the discovery of a molybdenum catalyst with bromide incorporation. [100] Further investigations indicated a chloridesubstituted molybdenum aryloxy catalyst, 22, easily performed the cross metathesis of these problematic substrates ( Figure 14). [100,101] Schrock, Hoveyda, and coworkers were also interested in Z-1,1,1,4,4,4-hexafluoro-2-butene as a cross metathesis …”

“…[100] Further investigations indicated a chloridesubstituted molybdenum aryloxy catalyst, 22, easily performed the cross metathesis of these problematic substrates ( Figure 14). [100,101] Schrock, Hoveyda, and coworkers were also interested in Z-1,1,1,4,4,4-hexafluoro-2-butene as a cross metathesis …”

“…[100] Employment of hexafluorobutene would allow access to a wide scope of substrates that possess a trifluoromethyl group, privileged molecules in the pharmaceutical and agrochemical industries. [98,99] Moreover, the synthesis of trifluoromethyl substituted olefins is limited, with these methods providing poor stereoselectivity or the thermodynamically favored E-product.…”