Abstract
Hafnium(IV) triflate (Hf(OTf)4) has been identified as a potent catalyst for the direct three-component synthesis of β-carbamate ketones. This new method, featuring a low catalyst loading, fast reaction rate, and solvent-free conditions, provided facile access to a diversity of carbamate-protected Mannich bases. A mechanistic investigation indicated that the three-component reaction proceeds via sequential aldol condensation and aza-Michael addition, but not the Mannich-type pathway.
Highlights
Introduction β-Amino ketones, commonly known as Mannich bases, represent an important class of synthetic scaffold [1,2,3,4,5] that has been widely employed in the synthesis of pharmaceutical agents [6,7,8] and natural products [9,10]
It has been reported that the replacement of amine substrates with less reactive carbamates under the same Mannich reaction conditions typically results in significantly lowered yields [15,16]
We found that hafnium(IV) triflate (Hf(OTf)4) is a highly potent Lewis acid catalyst for many reactions involving the activation of carbonyl [25], such as the selective anomeric deacetylation of peracetylated saccharides [26], the Biginelli reaction [27], and the synthesis of fluorinated benzimidazolines [28] and pyrimido[2,1-b][1,3]benzothiazoles [29,30]
Summary
We tested the reaction between Cbz-NH2 and chalcone in the presence or absence of Hf(OTf) (Scheme 1D). The experimental results showed that the two components did not react in the absence of a catalyst. Hf(OTf) catalyzed the highly efficient conversion to 1 (99%, 1 h). This result is supported by the previous reports on the catalytic aza-Michael addition of carbamates to enones [32,41,42,43]. It is proposed that the Hf(OTf)4-catalyzed three-component reaction proceeds via sequential aldol condensation and aza-Michael. * denotes the control experiment results without Hf(OTf) catalyst
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