Lithiation–Electrophilic Substitution of N‐Thiopivaloylazetidine

Abstract

Sechzehn und vier: Die wenig erforschte N‐Thiopivaloyl‐Gruppe ist entscheidend für die effiziente α‐Lithiierung eines Azetidinrings und die anschließende Einführung verschiedenartiger Elektrophile. In Gegenwart chiraler Liganden gelangen die ersten enantioselektiven elektrophilen Substitutionen an einem viergliedrigen Ring.

Direct α‐Functionalization of Saturated Cyclic Amines

“…Hodgson and Kloesges have reported the organolithiummediated a-functionalization of N-thiopivaloyl azetidine (81). [43] Their work began with deprotonation studies of the N-Boc-protected azetidine, but lithiation was found to be unsuccessful (LDA, LTMP or sBuLi), and attention was shifted to the use of other protecting/activating groups. While N-sulfinylazetidine (SOtBu), N-tert-butylsulfonyl (SO 2 tBu) and N-(diethylphosphonyl) (POA C H T U N G T R E N N U N G (OEt) 2 ) all gave poor lithiation results, the N-thiopivaloyl group allowed for successful lithiation of azetidine with sBuLi and TMEDA, as quenching with MeOD gave N-thiopivaloyl-2-deuteroazetidine (82 a) in good yield (Scheme 45).…”

“…This was presumably due a lack of coordination of Fe to the substrate, which might also indicate that no imine intermediate is involved in this specific case. Despite the excess substrate required, the Cu-catalyzed methodology for the coupling of unprotected tetrahydroisoquinoline was extended to the coupling with pyrroles 316-318, yielding products 319-321 in moderate yield (27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)Scheme 74). The role of the oxidant was examined and studies performed in the absence of oxi-dant with a stoichiometric quantity of Cu (irrespective of its oxidation state) or with TBHP as oxidant in the absence of Cu, showed no product formation, suggesting that the oxidant is not only required to reoxidize Cu I to Cu II in the catalytic cycle.…”

“…Hodgson and Kloesges have reported the organolithium‐mediated α‐functionalization of N ‐thiopivaloyl azetidine ( 81 ) 43. Their work began with deprotonation studies of the N ‐Boc‐protected azetidine, but lithiation was found to be unsuccessful (LDA, LTMP or s BuLi), and attention was shifted to the use of other protecting/activating groups.…”