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

Abstract

The azetidine moiety is a privileged motif in medicinal chemistry and new methods that access them efficiently are highly sought after. Towards this goal, we have found that azabicyclo[1.1.0]butyl carbinols, readily 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 a semipinacol rearrangement to give keto 1,3,3‐substituted azetidines. More than 20 examples were explored, enabling us to evaluate selectivity and the migratory aptitude of different groups. Alternatively, treatment of the same alcohols with benzyl chloroformate in the presence of NaI led to iodohydrin intermediates which gave spiroepoxy azetidines upon treatment with base. The electronic nature of the activating agent dictates which pathway operates.

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

“…The rapid assembly of 2 was achieved from dibromoamine 59 , in which two consecutive nucleophilic displacement reactions assemble the aza‐bicycle, before a final deprotonation of the bridgehead C−H bond with s BuLi/TMEDA delivers the carbenoid fragment. In a study performed concurrently with that reported by Wipf and coworkers (see Scheme 13), [100] these azabicyclo[1.1.0]butyl carbinols ( 60 ) were demonstrated to, upon trifluoroacetylation of the tertiary amine, undergo a strain‐promoted semi‐pinacol rearrangement and deliver keto 1,3,3‐substituted azetidines ( 61 ) [106] . Alternatively, treatment of the same intermediates with benzyl chloroformate in the presence of NaI led to iodohydrin intermediates 62 which could generate spiroepoxy azetidines ( 63 ) in a base‐promoted ring‐closure reaction.…”

“…This is more a representation of the lack of attention that this fragment has received rather than a reflection of its reactivity profile which, when explored, has been demonstrated to react with a similarly broad range of electrophiles [33] . An example of the unique reactivity that intermediates accessed from metalated azabicyclo[1.1.0]butanes can display was reported by Aggarwal and coworkers in 2021 (Scheme 15a) [106] . The intermediates in question, azabicyclo[1.1.0]butyl carbinols ( 60 ), could be rapidly synthesized in a single step via the addition of azabicyclo[1.1.0]butyl lithium ( 2 ) to a range of aldehydes and ketones.…”

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

“…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. However, cyclization to form the corresponding 7-membered ring product 4 s occurred in only trace amounts.…”

“…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][16][17] Pleasingly, this allowed the single-step construction of a wide variety of ABB-ketones bearing a (3 ac), b (3 d-q), g (3 r), and d (3 s) silyl-protected alcohols (Scheme 1). In general, higher yields were obtained when using Weinreb amides (2, LG = N(Me)OMe) as the electrophile; however, in the case of a-oxy ketone products 3 a-c and aryl ketone products 3 t-v, moderate to good yields could also be obtained when readily available carboxylate esters (2, LG = OMe, OEt) were used.…”

“…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] With a range of silyl ether-containing ABB-ketones in hand, we subsequently investigated the proposed spirocyclization reaction. ABB-ketone 3 a was selected as the model substrate, as azaspiro [3.3]heptanes are highly sought-after in drug discovery programs due to their favorable pharmacokinetic properties compared to commonly employed heterocyclic isosteres.…”