Mn-Mediated Radical-Ionic Annulations of Chiral N-Acylhydrazones

Abstract

Sequencing a free radical addition and nucleophilic substitution enables [3 + 2] and [4 + 2] annulations of N-acylhydrazones to afford substituted pyrrolidines and piperidines. Photolysis of alkyl iodides in the presence of Mn2(CO)10 leads to chemoselective iodine atom abstraction and radical addition to N-acylhydrazones without affecting alkyl chloride functionality. Using radical precursors or acceptors bearing a suitably positioned alkyl chloride, the radical addition is followed by further bond construction enabled by radical-polar crossover. After the alkyl radical adds to the imine bond, the resulting N-nucleophile displaces the alkyl chloride leaving group via 5-exo-tet or 6-exo-tet cyclizations, furnishing either pyrrolidine or piperidine, respectively. When both 5-exo-tet and 6-exo-tet pathways are available, the 5-exo-tet cyclization is preferred. Isolation of the intermediate radical adduct, still bearing the alkyl chloride functionality, confirms the order of events in this radical-polar crossover annulation. A chiral oxazolidinone stereocontrol element in the N-acylhydrazones provides excellent stereocontrol in these reactions.

Stereoselective access to tubuphenylalanine and tubuvaline: improved Mn-mediated radical additions and assembly of a tubulysin tetrapeptide analog

“…Advances in this Mn-mediated radical addition chemistry attributed to this synthetic effort are (a) primary alkyl addition in the presence of unprotected hydroxyl functionality to access tubuphenylalanine in high yield, (b) avoidance of E1cb-type elimination of β-alkoxy functionality in a tubuvaline precursor by employing non-basic isopropyl radical addition to the C=N bond, and (c) an alternative procedure involving slow addition of Mn 2 (CO) 10 to improve the yield of 10 . Taken together with our previous Mn-mediated coupling studies, 30 , 31 , 36 – 41 these advances broaden the scope and functional group compatibility of Mn-mediated radical additions to hydrazones, cementing the viability of this reaction for complex target-directed synthesis.…”

“… 32 – 35 The availability of efficient primary radical addition has opened many new synthetic applications; with earlier methods, primary alkyl radicals were prone to premature reduction or other side reactions (e.g., addition of ethyl radical under triethylborane or diethylzinc initiation). 20 – 26 The functional group tolerance and non-basic conditions of this method show excellent potential for synthesis of multifunctional amines; 36 – 41 the tubulysin γ-amino acids would test this potential. Indeed, our initial studies on tubulysins achieved preparation of Tuv precursor A and Tup itself ( B ) via these Mn-mediated radical addition reactions.…”

Photoinitiated Three-Component α-Perfluoroalkyl-β-heteroarylation of Unactivated Alkenes via Electron Catalysis

“…2,3 Along these lines, reductive radical addition to imines, oxime ethers, and hydrazones has been well explored (Scheme 1a). 3 N-Radicals generated upon radical addition to such C=N bonds can either be reduced by a H atom transfer reagent or by a single-electron-transfer (SET) process followed by protonation to give amines, alkoxyamines, or hydrazines. Recently, radical α-C(sp 2 )–H functionalization in N , N -dialkylhydrazones has gained attention (Scheme 1b).…”

Synthesis of Chiral Amines by C–C Bond Formation with Photoredox Catalysis

“…81 With [Ir{dF(CF 3 ) 2 ppy} 2 (bpy)]PF 6 as the photocatalyst, this tandem process entails radical addition by the mechanism of Scheme 39, followed by cyclization of the adduct via N-nucleophilic substitution of the bromide. 82…”