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

Abstract

The azetidine moiety is ap rivileged motif in medicinal chemistry and new methods that access them efficiently are highly sought after.T owards this goal, we have found that azabicyclo[1.1.0]butyl carbinols,r eadily obtained from the highly strained azabicyclo[1.1.0]butane (ABB), can undergo divergent strain-release reactions upon N-activation. Treatment with trifluoroacetic anhydride or triflic anhydride triggered as emipinacol rearrangement to give keto 1,3,3substituted azetidines.M ore than 20 examples were explored, enabling us to evaluate selectivity and the migratory aptitude of different groups.A lternatively,t reatment of the same alcohols with benzyl chloroformate in the presence of NaI led to iodohydrin intermediates whichg ave spiroepoxya zetidines upon treatment with base.T he electronic nature of the activating agent dictates whichp athwayoperates.

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 .…”

“…Indeed, this was shown to be the case with azetidine spiro‐tetralin 4 a ′ successfully synthesized in 56 % yield (Scheme 1 b). Despite employing conditions known to promote the semi‐pinacol rearrangement for ABB‐carbinols, [10a] such products were not observed from 2 a , highlighting the importance of protecting the hydroxy group to achieve the desired reactivity. This acylation strategy limits the functionality installed on the azetidine nitrogen to that of the specific acylating agent.…”

Strain‐Release Driven Spirocyclization of Azabicyclo[1.1.0]butyl Ketones

“…However, in the synthesis of several α‐ and β‐oxy ketones ( 3 a – f ), and aryl ketones 3 t – v , TMS ethers were too labile under the reaction conditions, necessitating the installation of more robust protecting groups (TES/TBS). Surprisingly, ABB‐ketones 3 a – v were found to be stable to chromatographic purification, in contrast to related azabicyclo[1.1.0]butyl carbinols [16] …”

“…We began by investigating the synthesis of ABB‐ketones 3 by the reaction of carboxylic acid derivatives 2 with ABB‐Li ( 1 ), which was formed in situ from commercially available ammonium salt 5 [15–17] . Pleasingly, this allowed the single‐step construction of a wide variety of ABB‐ketones bearing α ( 3 a – c ), β ( 3 d – q ), γ ( 3 r ), and δ ( 3 s ) silyl‐protected alcohols (Scheme 1).…”

“…In addition to the formation of trifluoroacetyl‐protected azetidines, the synthesis of sulfonamide products 4 aa , 4 bb and 4 cc was achieved by employing triflic anhydride as the activator, albeit with decreased yields due to competing nucleophilic substitution at the bridgehead carbon of the ABB by the triflate anion (see Table 1, entry 4). Despite the weak nucleophilic character of the triflate anion, addition is nevertheless observed, presumably due to the increased electrophilicity of the ABB bridgehead carbon upon activation with triflic anhydride, resulting in a less selective reaction [16] . Further extension of the carbon chain gave access to oxa‐azaspiro[3.5]nonane 4 r in 90 % yield.…”