Flow Technology for Telescoped Generation, Lithiation and Electrophilic (C₃) Functionalization of Highly Strained 1‐Azabicyclo[1.1.0]butanes

Abstract

Strained compounds are privileged moieties in modern synthesis. In this context, 1‐azabicyclo[1.1.0]butanes are appealing structural motifs that can be employed as click reagents or precursors to azetidines. We herein report the first telescoped continuous flow protocol for the generation, lithiation, and electrophilic trapping of 1‐azabicyclo[1.1.0]butanes. The flow method allows for exquisite control of the reaction parameters, and the process operates at higher temperatures and safer conditions with respect to batch mode. The efficiency of this intramolecular cyclization/C3‐lithiation/electrophilic quenching flow sequence is documented with more than 20 examples.

Sustainable continuous flow synthesis of β-aminocarbonyls via acid-catalyzed hydration of N-Boc-2-azetines

“…Next, by using the optimal conditions reported in Table 1, entry 3, we decided to explore the scope of the reaction for several C2-functionalized azetines 2 prepared using our previously developed continuous flow protocol. 22 As reported in Scheme 4, the process proceeds under mild conditions using oxalic acid in CH 2 Cl 2 at 25 °C allowing for the preparation of β-aminocarbonyls 4a–z in almost quantitative yields. The protocol was found to be highly efficient regardless of the nature of the substituent installed at the C2 position of the N -Boc-2-azetines ( 2a–z ) and occurred with high chemoselectivity and functional group tolerance.…”

Divergent, Strain‐Release Reactions of Azabicyclo[1.1.0]butyl Carbinols: Semipinacol or Spiroepoxy Azetidine Formation

“…We began our investigation by studying the reaction of ABB-Li with acetophenone (Scheme 2). [14] ABB-Li was formed in situ by the sequential reaction of amine salt 9 with phenyllithium and sec-butyllithium, [8a] and subsequently reacted with acetophenone at À78 8 8Ctoform ABB-carbinol 5a in good yield. This procedure was successfully applied to awide range of ketones and aldehydes.T he alcohol products were stable to aqueous work-up and could be stored at À18 8 8C with no evidence of degradation.…”

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

“…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.…”