Direct Alkylation of 1-Azabicyclo[1.1.0]butanes

Abstract

The facile synthesis of functionalized azetidines has been an ongoing challenge. Here, we report a general method to directly alkylate 1-azabicyclo[1.1.0]butane (ABB) with organometal reagents in the presence of Cu(OTf) 2 to rapidly prepare bis-functionalized azetidines. This method allows for the preparation of azetidines bearing alkyl, allyl, vinyl, and benzyl groups. This catalyst system was extended to aziridines and spirocycles. Several building blocks and druglike compounds were prepared in rapid fashion and in good yield.

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

“…In particular, the use of “spring‐loaded” hetero‐ and carbocycles as “click reagents” for rapid and direct installation of small ring bioisosters onto heteroatoms was emphasized, including applications of this strategy in medicinal chemistry. Among such strained compounds, azabicyclo[1.1.0]butanes ( ABB s) are emerging as useful reagents for the preparation of azetidines [3] . In fact, 1,3‐functionalized azetidines can be obtained by strain‐release of azabicyclo[1.1.0]butanes (Figure 1 a).…”

Divergent Functionalizations of Azetidines and Unsaturated Azetidines

“…This strategy for installing 3‐substituted azetidines was also shown to be tolerated by several late‐stage pharmaceutical reagents. More recently, Gianatassio and Kadish have expanded this route to substituted azetidines through the inclusion of carbon nucleophiles with the addition of a copper catalyst (Scheme C) . In an umpolung approach, Aggarwal and coworkers have also reported that nucleophilic 53 is accessible from either isolable 55 or in situ generated 48 and that addition of this strained nucleophilic reagent to boronate esters triggers a 1,2‐metallate rearrangement to give 56 .…”

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

“…First prepared in 1969, [7] the highly strained building block was shown to react with electrophiles such as tosyl chloride, [5a] through activation of the ABB nitrogen, followed by nucleophilic addition at the bridgehead carbon (Scheme 1 b). More recently, it was demonstrated that ABB could react with strong nucleophiles such as turbo amides (Scheme 1 b) [5b] or organocuprates [5d] to enable rapid access to diverse 1,3‐substituted azetidines. We recently reported the preparation of azabicyclo[1.1.0]butyllithium (ABB‐Li, 2 ) by the facile lithiation of 1 at the bridgehead position with TMEDA‐ligated sec ‐butyllithium (Scheme 1 b).…”