Hybrid Radical Ionic Annulation

The hybrid radical ionic annulation was envisioned to be useful for piperidine 

4 chloro iodobutane afforded the acyclic adduct 39 in 66% yield with a diastereomer 

Reaction conditions (1) Aldehyde or acetal (5 10 equiv), 7a, p-toluenesulfonic acid, CH2CI2, rt. (2) Hydrazone in deoxygenated CH2CI2 (0.1 M), InCl j (2.2 equiv), Mn2(CO),o (1 2 equiv), R X (10 equiv), hv (300nm, pyrex), 1 2 d, about 35 C. 

2 Precursors Containing Hydroxyl or Protected Hydroxyl Croups 

The hybrid radical ionic annulation illustrates that precursors containing additional electrophilic functionality can be used to synthetic advantage. A number of other examples of functional group compatibility have been examined, including oxygen containing radical precursors and acceptors. 

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The simple piperidine alkaloid coniine (for selected asymmetric syntheses of coniine see [22, 81-85]) offered a preliminary test case for hybrid radical-ionic annulation in alkaloid synthesis. From butyraldehyde hydrazone and 4-chloro-iodobutane (Scheme 4), manganese-mediated photolysis afforded the acyclic adduct in 66% yield (dr 95 5) the cyclization did not occur in situ [69, 70]. Nevertheless, Finkelstein conditions afforded the piperidine, and reductive removal of the auxiliary afforded coniine in 34% overall yield for four steps. This reaction sequence enables a direct comparison between radical- and carbanion-based syntheses using the same retrosynthetic disconnection an alternative carbanion approach required nine to ten steps [81, 85]. The potential for improved efficiency through novel radical addition strategies becomes quite evident in such comparisons where multifunctional precursors are employed. 

Our approach to the antimalarial alkaloid quinine focuses on strategic application of the manganese-mediated hybrid radical-ionic annulation. Retrosyntheti-cally, this is illustrated (Scheme 5) by disconnection of either of two C-C bonds... 

Scheme 4 Hybrid radical-ionic annulation route to (R)-coniine...

Interestingly, the 3 chloro 1 iodopropane addition (Table 2.6, entry 9) led exclusively to pyrrolidine 37 (Scheme 2.4) none ofthe acyclic adducts was found [31]. Presumably, radical addition was followed by in situ Sn2 type cyclization. The same type ofcyclization, giving the epimeric pyrrolidine (epi 37), occurs upon ethyl addition to the 3 chlorobu tyraldehyde hydrazone (Table 2.6, entry 18). These reactions are hybrid radical ionic annulations of the C=N bond, a new class of radical polar crossover reactions [32]. 

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