C‐H Functionalization of Amino Alcohols by Osmium Tetroxide/NMO or TPAP/NMO: Protecting Group‐Free Synthesis of Indolizidines (–)‐223AB and 3‐epi‐(–)‐223AB

Abstract

The oxidative cyclization of amino alcohols by osmium tetroxide/NMO or tetrapropylammonium perruthenate (TPAP)/NMO was found to provide an N,O-acetal moietyThe functionalization of a carbon adjacent to a tertiary amine nitrogen via a C(sp 3 )-H activation has been developed over the past decade, and such methods include oxidative cross-dehydrogenative coupling (CDC) reactions, [1,2] electro-oxidative activations and photoredox reactions. [3,4] In these processes, the generated iminium cations are important intermediates for the subsequent C-C, C-O, and C-N bond formations. In particular, the formation of a C-O bond by the addition of an oxygen nucleophile to the iminium cation gives an N,O-acetal moiety. Such manipulation can simultaneously activate and protect a specific carbon, thus providing greater efficiency and flexibility for subsequent synthetic transformations. Since the N,O-acetal moiety can be assembled or cleaved whenever carbon activation or subsequent functionalization is needed, tedious protection/deprotection steps in the synthetic sequence can be avoided.Unfortunately, existing N,O-acetal generation strategies involving the trapping of oxygen by the iminium cation are better suited to the addition of phenolic oxygens via Cu(OAc) 2 , Ag 2 O or I 2 /H 2 O 2 mediated oxidations (Scheme 1a), [5][6][7] or reactions of aryl aldehydes/aryl alkyl ketones with amines under metal and oxidant free conditions (Scheme 1b). [8] The limited examples involving nonphenolic hydroxyl groups include the electrooxidative cyclization or Ir(ppy) 2 (dtb-bpy)PF 6 catalyzed photooxidation of hydroquinoyl and hydroisoquinoyl alcohols (Scheme 1c), [4b,4c] and FeCl 3 [9] or CHDFe(CO) 3[10] mediated oxidations of saturated amino alcohols (Scheme 1d). Herein, we disclosed two novel and general procedures for the oxidative cyclization of saturated amino alcohols. When amino alcohols 1a and 1b were used as test substrates, we were surprised to find that a catalytic amount of OsO 4 with NMO or a catalytic amount of tetrapropylammonium perruthenate (TPAP) with NMO are ef- [a]