Selective 1,2-Additions with LaCl3·2LiCl

Aaron Thornton

While the 1,2-addition of Grignard reagents to ketones is undoubtedly a powerful transformation, oftentimes selectivity issues arising from competitive alpha-deprotonation detract from the use of these reagents. Various methods have been developed to address this shortcoming, including the use of CeCl₃ and other Lewis acidic salts. However, because of the heterogeneous nature of these reagents, it is often difficult to obtain adequate selectivity. With this in mind, the lab of Professor Paul Knochel has shown that LaCl₃•2LiCl (703559) may be used to attenuate the basicity of Grignard reagents, in turn preventing competitive enolization side reactions while leading to a powerful method for the selective 1,2-addition of Grignard reagents to ketones. In addition to enolizable ketones, even sterically hindered ketones, as well as Michael acceptors and unactivated imines can undergo 1,2-additions selectively to provide the desired addition products (Table 1).¹

Table 1. LaCl3•2LiCl mediated addition to ketones.(703559)

Subsequent to these initial studies with LaCl₃•2LiCl, Knochel and coworkers reported that sub-stoichiometric quantities of the lanthanide salt are sufficient to promote the desired 1,2-addition, as demonstrated by the addition of i-PrMgCl•LiCl to unactivated imines (Scheme 1). This protocol is amenable to the use of alkyl, aryl, and heteroaryl Grignard reagents.²

Scheme 1. 1,2-Addition of organomagnesium reagents in the presence of catalytic LaCl3•2LiCl.

Advantages of LaCl₃•2LiCl:

• No pretreatment procedures necessary
• Easy handling of reagents and reaction setup
• Homogeneous reaction conditions
• Improved selectivity and reactivity providing better yields and decreased reaction times

References

1. Krasovskiy A, Kopp F, Knochel P. 2006. Soluble Lanthanide Salts (LnCl3?2 LiCl) for the Improved Addition of Organomagnesium Reagents to Carbonyl Compounds. Angew. Chem. Int. Ed.. 45(3):497-500. https://doi.org/10.1002/anie.200502485

2. Knochel P, Metzger A, Gavryushin A. LaCl3×2LiCl-CatalyzedAddition of Grignard Reagents to Ketones. Synlett. 2009(09):1433-1436. https://doi.org/10.1055/s-0029-1217169