Methods for the Synthesis of Substituted Azetines

Abstract

Spurred on by the recent emerging interest from the chemical community for unsaturated four-membered heterocycles, an unprecedented approach to nitrogen-containing four-membered rings has been designed. 3,4-Disubstituted 2-azetines were synthesized from commercially available substrates, allowing for a straightforward access to a new library of chiral functionalized azetidines and amino alcohols. This original approach was applied to efficiently prepare functionalized azobenzenes, an emerging class of molecules with a large potential in photopharmacology.

Divergent Functionalizations of Azetidines and Unsaturated Azetidines

“…Secondary alcohol 95 d was also observed to undergo tautomerization to give ketone‐substituted azetidine 96 when subjected to mildly acidic CDCl 3 . Didier and coworkers later discovered that this approach can be used to prepare 2,3‐disubstituted 1,2‐dihydroazetes 99 from 98 , which are easily accessible via the addition of a Grignard reagent to 97 (Scheme C) . These studies established general and versatile methods for the preparation of substituted 1,2‐dihydroazetes via electrophilic trapping of intermediates such as 94 and provided preliminary results for expanding this methodology through transmetallation.…”

“…While 95 h was formed in low yield, this initial result provided proof of principle for these desirable transformations. Didier and coworkers further advanced this idea through the development of a high‐yielding sequential elimination, lithiation, and Suzuki coupling process (Scheme B) . When 98 are treated with s ‐BuLi, the resulting lithiated 1,2‐dihydroazetes can be trapped with B(Oi−Pr) 3 to form 99 c .…”

“…While reports from Hodgson and Didier have primarily focused on the divergent synthesis of 1,2‐dihydroazetes, several isolated and recent results have further showcased the potential of using these products for the diversity‐oriented synthesis of azetidines. Didier and coworkers showed that 2,3‐disubstituted 1,2‐dihydroazete 99 h can be hydrogenated to give cis ‐azetidine 100 and that the N ‐Boc substituent of 100 can be easily removed under mild conditions (Scheme ) . Surprisingly, when racemic 99 i was subjected to hydrogenation conditions, secondary interactions with the Pd/C catalyst resulted in diastereoselective formation of 102 .…”

“…Didier and coworkers showed that 2,3‐disubstituted 1,2‐dihydroazete 99 h can be hydrogenated to give cis ‐azetidine 100 and that the N ‐Boc substituent of 100 can be easily removed under mild conditions (Scheme ) . Surprisingly, when racemic 99 i was subjected to hydrogenation conditions, secondary interactions with the Pd/C catalyst resulted in diastereoselective formation of 102 . Beyond reduction, Didier and coworkers have also used their sequential elimination, lithiation, and Suzuki cross coupling process to access 1,2‐dihydroazete dienes for cycloaddition processes .…”

Synthesis of Chiral Tetrasubstituted Azetidines from Donor–Acceptor Azetines via Asymmetric Copper(I)‐Catalyzed Imido‐Ylide [3+1]‐Cycloaddition with Metallo‐Enolcarbenes

“…[2] These relatively high energy compounds have not been widely explored because of limited synthetic methods for their formation and because their well-recognized ability to undergo four-electron electrocyclic ring-opening to 1-aza-1,3-butadienes. [3] Available methods for 2-azetine synthesis include those from already-formed four-membered ring heterocycles (3-methoxyazetidine derivatives and 3-azetidinones), [4] vinyldiazo compounds via aziridination/ring expansion reactions, [5] as well as from benzyne via [2+ +2]-cycloaddition [6] or allenyl imides with imines [7] (Scheme 1a,b). However,n one of the available methods are suitable for the synthesis of chiral 2-azetines.…”