Selective Synthesis of Trifluoromethyl β‐Lactams by a Zn‐Promoted 2‐Bromo Ester Addition on C‐CF₃‐Substituted Aldimines

Abstract

Starting from C‐CF3‐substituted aldimines, trifluoromethyl β‐lactams were obtained as only products in the reaction with some α‐bromo esters in the presence of activated zinc dust. Different solvents, molar ratios, and temperature were tested to determine the best reaction conditions that led only to desired cyclic compounds. The influence of another ester group on the aldimine chain and the reaction diastereoselectivity were also considered.

Direct Access to Substituted 4-CF3 β-Lactams at the C-3 Position

“…Herein, we disclose the straightforward synthesis of mono- and difunctionalized 4-CF 3 β-lactams at the C-3 position. First, 4-CF 3 β-lactams 1 and 2 were synthesized according to the literature (Trulli et al, 2018), and the same method was applied to the synthesis of the N -PMBn protected 4-CF 3 β-lactam 3 . Then, we attempted the C-3 monodeprotonation of the 4-CF 3 β-lactams 1–3 (Trulli et al, 2018) with diverse bases such as LDA, LiHMDS, and LTMP.…”

“…First, 4-CF 3 β-lactams 1 and 2 were synthesized according to the literature (Trulli et al, 2018), and the same method was applied to the synthesis of the N -PMBn protected 4-CF 3 β-lactam 3 . Then, we attempted the C-3 monodeprotonation of the 4-CF 3 β-lactams 1–3 (Trulli et al, 2018) with diverse bases such as LDA, LiHMDS, and LTMP. Thus, the addition of benzaldehyde at different conditions (temperature, time, concentration of base) was conducted.…”

“…The C-3 monosubstituted 4-CF 3 β-lactams 9 and 18 have been prepared using the Reformatsky reaction between CF 3 -aldimine and methyl- and phenyl-α-bromo esters (Scheme 3). The 3-Me 4-CF 3 β-lactams 9 were prepared according to the literature (Trulli et al, 2018) but with shorter reaction time (6 h). For this reason, we observed different ratio of cis (3S * ,4S * ) and trans (3R * ,4S * ) isomers (0.5:1, respectively) than was reported.…”

“…Although fluorine-containing compounds have been widely used in the field of medicinal chemistry (Wang et al, 2014; Zhu et al, 2014; Zhou et al, 2016) due to their pharmacological properties, 4-CF 3 monobactams functionalized at C-3 are slightly exploited. The synthesis of 4-CF 3 monosubstituted β-lactams at the C-3 position are reported and prepared according to different ways: Staudinger reaction (Guanti et al, 1985; Abouabdellah et al, 1997; Petrik et al, 2011), ring expansion of aziridines via halogen-metal exchange (Decamps et al, 2014), Kinugasa reaction (Kowalski et al, 2016), and the Reformatsky reaction (Trulli et al, 2018). The alkylation reaction with non-fluorinated β-lactams using lithium amide, such as LDA and Li/KHDMS, to obtain the alkylated products at C-3 was well documented in the literature (Kuhlein and Jensen, 1974; Kamath and Ojima, 2012; Deketelaere et al, 2017).…”

Stereocontrolled synthesis of fluorine-containing functionalized β-lactam derivatives through cross-metathesis reactions

“…Thanks to the utility of β-lactams, this interest has also been extended to fluorine-containing azetidin-2-ones. Such compounds are often synthesized by using a fluorinated reactant during heterocyclization [14][15][16][17][18][19], but late-stage fluorination (fluorine introduction after synthesizing the azetidinone skeleton) can also be applied [20]. β-Lactams expressed their importance in the synthesis of different fluorinated molecules such as sugar-βamino acid conjugates [15], amido esters [18], aminopropanes and heterocycles [17], as well as taxoids and β-amino acids [20].…”