Synthesis and Applications of 3‐Methylene‐4‐(trifluoromethyl)azetidin‐2‐ones as Building Blocks for the Preparation of Mono‐ and Spirocyclic 4‐CF₃‐β‐Lactams

Abstract

3-Methylene-4-(trifluoromethyl)azetidin-2-ones were efficientlyp repared from the corresponding 3-oxo-4trifluoromethyl-b-lactams and successfully evaluated as novel building blocks in organic synthesis. In particular, Michael additions, electrophilica dditions, and cycloadditions were applied to allow easy access to ab road variety of stereodefined mono-and spirocyclic 4-CF 3 -b-lactams as useful synthetic intermediates en route to av ariety of biologically relevant CF 3 -functionalized target structures.[a] H.

Synthesis of Novel Chiral Spiroisoxazolidine‐β‐Lactams from 6‐Alkylidenepenicillanates: A 1,3‐Dipolar Cycloaddition Approach

“…[10] More recently, while exploring the reactivity of alkylidene--lactams, Wang and Dao Thi have described the synthesis of novel spiroisoxazolidines from benzaldehydederived nitrones. [11] Nevertheless, all these advances were exclusively focused on the reactivity of alkylidenes derived from mono--lactams.…”

Use of 3-Hydroxy-4-(trifluoromethyl)azetidin-2-ones as Building Blocks for the Preparation of Trifluoromethyl-Containing Aminopropanes, 1,3-Oxazinan-2-ones, Aziridines, and 1,4-Dioxan-2-ones

“…In addition to the preparation of 3-hydroxy-4-trifluoromethyl-β-lactams 3a,b as described in our previous study, 8,10 a set of four new 3-hydroxy-4-trifluoromethyl-βlactams 3c-f was successfully synthesized, with slight modifications in the procedure. In the first step, 1-ethoxy-2,2,2-trifluoroethanol (1) was condensed with (a) isopropylamine in dichloromethane in the presence of MgSO 4 as drying agent and with (b) different arylamines (p-phenetidine, p-toluidine, 4-iodoaniline) in toluene in the presence of a catalytic amount of p-toluenesulfonic acid under Dean-Stark conditions.…”

“…9 Furthermore, an addition/elimination sequence applied to 3-oxo-βlactams III afforded 3-methylene-β-lactams IV as a fourth class of new building blocks, which were shown to be eligible substrates for Michael additions, electrophilic additions, and cycloadditions en route to a variety of stereodefined mono-and spirocyclic 4-trifluoromethyl-β-lactams. 10 In order to further demonstrate the broad diversity of these 4trifluoromethyl-β-lactam building blocks, we recently explored the synthetic applicability of 3-hydroxy-4-trifluoromethyl-β-lactams II. In particular, manipulation of the alcohol group enabled the construction of trifluoromethylcontaining ring-rearranged products, including aziridines through a ring-contraction protocol via 3-chloro-β-lactam intermediates and dioxan-2-ones via initial O-allylation, about which will be communicated in this paper.…”

Synthesis and reactivity of 4-(trifluoromethyl)azetidin-2-ones

“…The enolates of 3-benzyloxy-4-CF 3 -β-lactams 60, generated with LiHMDS in THF at -78 °C, were subjected to [1,2]-and ortho- [2,3] were prepared upon treatment of the corresponding diols, derived from the OsO 4mediated oxidation of 3-methylene-β-lactams 8, with triphosgene [38].…”

“…72% yield through the addition of methylmagnesium bromide across the cyclic ketone, followed by alcohol activation and elimination [35][36][37][38].…”