Titanium isopropoxide-mediated -selective synthesis of 3,4-substituted butyrolactones from CO

We report a Ti(OiPr) 4 -mediated multicomponent reaction, which produces 3,4-substituted cis -δ-lactones from alkyl magnesium chloride, benzaldehyde and CO 2 . The key intermediate, titanacyclopropane, is formed in situ from Ti(OiPr) 4 and a Grignard reagent, which enables 1,2-dinucleophilic reactivity that is used to insert carbon dioxide and an aldehyde. An alternative reaction route is also described where a primary alkene is used to create the titanacyclopropane. A computational analysis of the elementary steps shows that the carbon dioxide and the aldehyde insertion proceeds through an inner-sphere mechanism. A variety of cis -butyrolactones can be synthesized with up to 7 : 1 diastereoselectivity and 77% yield. Titanium-mediated 1,2-activation of Grignard reagents enables α and β insertion of carbon dioxide and arylaldehyde to prepare cis -3,4 butyrolactones.