Generation and Electrophile Trapping of N-Boc-2-lithio-2-azetine: Synthesis of 2-Substituted 2-Azetines

Abstract

s-BuLi-induced α-lithiation–elimination of LiOMe from N-Boc-3-methoxyazetidine and further in situ α-lithiation generates N-Boc-2-lithio-2-azetine which can be trapped with electrophiles, either directly (carbonyl or heteroatom electrophiles) or after transmetalation to copper (allowing allylations and propargylations), providing a concise access to 2-substituted 2-azetines.

trans‐Selective Aryldifluoroalkylation of Endocyclic Enecarbamates and Enamides by Nickel Catalysis

“…Notably, the strained four‐membered ring did not affect the reactivity of 2‐azetine 1 b , and allowed this nickel‐catalyzed tandem process with a series of arylzinc reagents efficiently (Scheme B). An array of dicarbofunctionalized azetidines 6 , which are difficult to access through conventional methods, could be achieved through this transformation with high efficiency and trans ‐selectivity (dr >20:1). Similarly, good functional group tolerance was observed ( 6 i , 6 j , 6 n ), even toward aryl chloride and heteroarenes ( 6 l , 6 s – 6 u ).…”

Divergent Functionalizations of Azetidines and Unsaturated Azetidines

“…The initial success of using elimination, lithiation, and electrophilic trapping to form substituted 1,2‐dihydroazetes 95 led to the development of processes to trap lithiated 1,2‐dihydroazetes in cross coupling transformations. As shown in Scheme A, Hodgson and coworkers reported the first example of a Negishi arylation by transmetallation of 94 to ZnCl 2 and subsequent treatment with a palladium catalyst and bromobenzene . While 95 h was formed in low yield, this initial result provided proof of principle for these desirable transformations.…”

“…While investigating the azetidine α‐lithiation and electrophilic trapping studies described above, Hodgson and coworkers discovered that treatment of 90 with s ‐BuLi results in the formation of 92 (Scheme A) . Further experimentation determined that addition of two equivalents of s ‐BuLi to 93 provides access to 2‐lithiated 1,2‐dihydroazete 94 and allows for the sequential addition of electrophiles to form 95 (Scheme B) . While a variety of electrophiles such as silyl halides, aldehydes, and halogens were determined to be compatible with this transformation (see 95 a – 95 d , Scheme ), the scope of the method was further expanded to include allylic and propargylic halides via transmetallation of the lithiated intermediate to CuCN (see 95 e – 95 g , Scheme B) .…”

“…Further experimentation determined that addition of two equivalents of s ‐BuLi to 93 provides access to 2‐lithiated 1,2‐dihydroazete 94 and allows for the sequential addition of electrophiles to form 95 (Scheme B) . While a variety of electrophiles such as silyl halides, aldehydes, and halogens were determined to be compatible with this transformation (see 95 a – 95 d , Scheme ), the scope of the method was further expanded to include allylic and propargylic halides via transmetallation of the lithiated intermediate to CuCN (see 95 e – 95 g , Scheme B) . Secondary alcohol 95 d was also observed to undergo tautomerization to give ketone‐substituted azetidine 96 when subjected to mildly acidic CDCl 3 .…”

One-Pot Preparation of Stable Organoboronate Reagents for the Functionalization of Unsaturated Four- and Five-Membered Carbo­- and Heterocycles

“…Azetinyllithium reagents were generated by α-lithiation of in situ formed azetines 2 using s-BuLi in the presence of TMEDA in THF at -78 °C, 14 and subsequently trapped with boron isopropoxide to give C. 15 Organoboronates A, B and C were then stored either in solution or neat at -20 °C or room temperature before being engaged in Suzuki cross-couplings (Scheme 2).…”