Four‐Component Strain‐Release‐Driven Synthesis of Functionalized Azetidines

Abstract

Despite the favorable properties that azetidine rings can engender on drug-compounds, methods for the diversity-oriented synthesis of azetidine-based structures are significantly underdeveloped. Herein, we report the successful realization of a multicomponent [1,2]-Brook rearrangement/strain-release-driven anion relay sequence and its application to the modular synthesis of substituted azetidines. The rapidity of the reaction, as confirmed by in situ infra-red spectroscopy, leverages the strain-release ring-opening of azabicyclo-[1.1.0]butane to drive the equilibrium of the Brook rearrangement. The three electrophilic coupling partners, added sequentially to azabicyclo[1.1.0]butyl-lithium, could be individually varied to access a diverse compound library. The utility of this methodology was demonstrated in a 4-step synthesis of the EP2 receptor antagonist PF-04418948.

Cation‐Promoted Strain‐Release‐Driven Access to Functionalized Azetidines from Azabicyclo[1.1.0]butanes

“…Strong nucleophiles (e.g., thiol, turbo‐amide, Grignard reagent or organocuprates) can add directly to bridgehead carbon of ABB without any definitive N‐activation and in conjunction to such C3 functionalization, strategies like S N Ar, Buchwald–Hartwig coupling or acylation/sulfonylation were used to leverage subsequent N1 functionalization [8d–h] . Recently, the Aggarwal group disclosed a suite of transformations using tailored C3‐substituted ABB derivatives (Scheme 1c), [9a–d] wherein a distinct nitrogen activation led to intramolecular rearrangement or annulation at C3 involving functional group(s) present at that position—affording N1/C3‐functionalized azetidines in tandem fashion.…”

“…The breadth of the current N/C3 functionalization strategy of ABB was extended to other differentially functionalized ABBs. For instance, 84 could be transformed into azetidines 85 and 86 (Scheme 5B) by N‐functionalization/C3‐Friedel–Crafts spirocyclization [9d] . Remarkably, when ABB‐carbinol 1 a was subjected to conditions conducive to in situ generation of an oxyallyl cation [20] from 87 , strain‐release‐driven functionalization of 1 a still formed 89 (Scheme 5C).…”

Synthesis and Applications of Bicyclo[1.1.0]butyl and Azabicyclo[1.1.0]butyl Organometallics

“…In a later study, Aggarwal and coworkers again harnessed the predictable reactivity between 2 and aldehydes to access aryl tethered azabicyclo[1.1.0]butanes 64 (Scheme 15b). [107] In this case, the semi-pinacol rearrangement of intermediate 64 In 2021, Luisi and coworkers reported the first continuous flow protocol for the generation of azabicyclo[1.1.0]butyl lithium 2, representing a considerable advancement in the synthesis of bicyclo[1.1.0]butyl organometallics (Scheme 16a). [108] The benefits of utilizing flow chemistry compared to the analogous batch process are numerous and include improved scalability, safer handling of pyrophoric materials and the ability to perform such a synthesis without the need for cryogenic temperatures.…”

“…Finally, Aggarwal and coworkers reported a multicomponent approach to azetidine synthesis which harnesses the inimitable reactivity of azabicyclo[1.1.0]butyl lithium (Scheme 17). [110] This protocol involved the coupling of 2 with acyl silanes which, upon [1,2]-Brook rearrangement and anion collapse to open the strained bicycle, delivered silyl enol ether 70. This intermediate could then react with an electrophile at nitrogen and, after aqueous workup, with a further electrophile at the silyl enol ether fragment.…”

Four‐Component Strain‐Release‐Driven Synthesis of Functionalized Azetidines

“…We began by investigating the synthesis of silyl enol ether 4 a in isolation (Table 1). To achieve this, ABB‐Li ( 1 ) was synthesized according to previous reports from dibromo‐amine 6 and TMEDA‐ligated s BuLi [8c, 9a] . Acetyltrimethylsilane ( 7 a ) was then added directly to 1 , which, upon nucleophilic addition, could participate in the desired [1,2]‐Brook rearrangement/strain‐release‐driven anion relay sequence.…”