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.

Development of a Continuous Flow Synthesis of 2-Substituted Azetines and 3-Substituted Azetidines by Using a Common Synthetic Precursor

“…The first reported synthesis of the azetidine ring dates to 1888, but interest in developing efficient synthetic methodologies for creating functionalized azetidines was raised only recently. On the other hand, such a relatively unexplored motif continues to stimulate organic chemists’ creativity . Our research group is involved in developing synthetic tactics involving metalated (i.e., lithiated) azetidines as useful intermediates for creating molecular diversity. , In addition, we became interested in the use of flow technology as a tool for taming, controlling, and using highly reactive organometallic intermediates .…”

Strain‐Release‐Driven Friedel–Crafts Spirocyclization of Azabicyclo[1.1.0]butanes

“…We began by investigating the synthesis of spirocyclization precursors 2 through the reaction of aryl‐tethered aldehydes and ketones 7 with ABB‐Li ( 1 ), formed in situ from dibromo‐amine 6 (Scheme 1 a). [14] Due to their instability towards chromatographic purification and the potential side reactions (semi‐pinacol rearrangement or epoxidation) that may occur upon electrophilic activation of the ABB fragment, [10a] we decided to alkylate the resulting ABB‐carbinols to provide alkyl ethers 2 .…”

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

“…a,b-Unsaturated aldehydes and ketones were also suitable starting materials under our reaction conditions, furnishing exclusively the 1,2-addition products 4 r and 4 s. Notably, the expected C3-functionalized 1-azabicyclo-[1.1.0]butane structure of 4 s could be confirmed by X-ray analysis (Scheme 1). [12] An imine was also evaluated as electrophile, furnishing strained amine 4 t. With a-chloroacetophenone as the substrate, electrophilic addition of ABB-Li to the carbonyl group was followed by intramolecular cyclization, providing epoxide 4 u in moderate yield.…”