Investigation of Grignard Reagent as an Advanced Base for Aza-Claisen Rearrangement

Abstract

Employing iPrMgCl as an advanced base instead of lithium hexamethyldisilazane (LHMDS) resulted in dramatic improvements in aza-Claisen rearrangement. This advance is considered responsible for the increased bulkiness of the alkoxide moiety (including magnesium cation and ligands), followed by a resultant conformational change of the transition state. To support this hypothesis, various substrates of aza-Claisen rearrangement were prepared and screened. In addition, a molecular dynamic simulation study was performed to investigate and compare the structural stability of reaction intermediates.

Synthesis of Tetrabenazine and Its Derivatives, Pursuing Efficiency and Selectivity

“…The use of LHMDS (Lithium bis(trimethylsilyl)amide) in refluxing toluene afforded the desired 10-membered lactam 35 in 25% yield, but surprisingly, the Grignard reagent resulted in an improved deprotonation and concomitant aza-Claisen rearrangement reaction, which gave product 35 in 78% yield. Further studies revealed this superior result originates from the steric interaction between the alkoxide-cation complex and bulky isobutyl side chain [54]. Based on this finding, more examples showed the Grignard reagent could be used as an advanced base for the aza-Claisen rearrangement.…”

Grignard Reagents as Niche Bases in the Synthesis of Pharmaceutically Relevant Molecules

“…[35] The ACR derived alkaloid skeletons serve as very important synthetic precursors for natural products and APIs. [35][36][37][38][39][40][41][42][43] Another distinctive feature of this reaction is, by transforming the chirality to other inaccessible places it helps in generating remote stereogenic centers in highly selective manner. Nevertheless, these reactions often require harsh reaction conditions and offers low yields.…”

“…These observa-tions were well utilized for accessing bioactive natural products and APIs. [35][36][37][38][39][40][41][42][43] For example, Songet al [36] studied the general applicability of ACR reactionsin substrates of type 63 for accessing various substituted 10-membered lactams 64 (Scheme 17). The reaction was studied in presence of various solvents and bases such as LiHMDS, NaHMDS, KHMDS, t BuMgBr, i PrMgBr, EtMgBr, etc.…”

“…It was observed that i PrMgBr in refluxing benzene gave the best results in terms of yields and selectivity. [36]…”

“…It has been observed that Grignard reagents such as i PrMgCl gave better results in the ACR than other metal bases like LiHMDS. These observations were well utilized for accessing bioactive natural products and APIs [35–43] …”