Mn-Mediated Coupling of Alkyl Iodides and Chiral N-Acylhydrazones:  Optimization, Scope, and Evidence for a Radical Mechanism

Abstract

Stereoselective radical additions have excellent potential as mild, nonbasic carbon-carbon bond constructions for direct asymmetric amine synthesis. Efficient intermolecular radical addition to C=N bonds with acyclic stereocontrol has previously been limited mainly to secondary and tertiary radicals, a serious limitation from the perspective of synthetic applications. Here, we provide full details of the use of photolysis with manganese carbonyl to mediate stereoselective intermolecular radical addition to N-acylhydrazones. Photolysis (300 nm) of alkyl halides and hydrazones in the presence of Mn2(CO)10 and InCl(3) as a Lewis acid led to reductive radical addition; diastereomer ratios ranged from 93:7 to 98:2 at ca. 35 degrees C. The reaction tolerates additional functionality in either reactant, enabling subsequent transformations as shown in an efficient asymmetric synthesis of coniine. A series of hydrazones bearing different substituents on the oxazolidinone auxiliary were compared; consistently high diastereocontrol revealed that the identity of the substituent had little practical effect on the diastereoselectivity. Further mechanistic control experiments confirmed the intermediacy of radicals and showed that independently prepared alkyl- or acylmanganese pentacarbonyl compounds do not undergo efficient addition to the N-acylhydrazones under thermal or photolytic (300 nm) conditions. These Mn-mediated conditions avoid toxic tin reagents and enable stereoselective intermolecular radical additions to C=N bonds with the broadest range of alkyl halides yet reported, including previously ineffective primary alkyl halides.

Radicals in organic synthesis. Part 1

“…Friestad has shown that manganese-mediated addition of alkyl radicals to chiral hydrazones occurs with excellent yields and diastereoselectivity. 271 The reaction tolerates a range of primary and secondary iodides as radical precursors, but fails to furnish any product with allyl, benzyl or tert-butyl bromides. The structure of the radical acceptor appears to be unimportant, and even a-branched alkyl imino compounds react in good yields.…”

Asymmetric Methods for Radical Addition to Imino Compounds

“…The manganese carbonyl reagent proved to be a dramatic improvement [31]. For ethyl iodide addition to 8a (Table 2.6), irradiation (300 nm) with Mn 2 (CO) 10 using InCl 3 as a Lewis acid furnished the ethyl adduct in 85% yield, much higher than with triethylborane or hexamethylditin.…”

“…Manganese-Mediated Coupling with Multifunctional Precursors 2.2.6.1 Hybrid Radical-Ionic Annulation Interestingly, the 3-chloro-1-iodopropane addition (Table 2.6, entry 9) led exclusively to pyrrolidine 37 (Scheme 2.4); none of the acyclic adducts was found [31]. Presumably, radicaladdition wasfollowedbyin situ S N 2-type cyclization.…”

“…The alkaloid coniine [33] (Scheme 2.5) offers a simple test case. Starting with the butyraldehyde hydrazone 38, Mn-mediated photolysis with 4-chloro-iodobutane afforded the acyclic adduct 39 in 66% yield with a diastereomer ratio of 95 : 5 [31]. In this case, Finkelstein conditions were needed for cyclization, Reaction conditions: (1) Aldehyde or acetal (5-10 equiv), 7a, p-toluenesulfonic acid, CH 2 Cl 2 , rt.…”

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

“…12 In our prior work on radical addition reactions of chiral Nacylhydrazones, we found that Mn-mediated additions of alkyl iodides to these CN acceptors proceed via addition of free carbon-centered radicals rather than organomanganese species. 13 The alkyl radicals are generated via a well-precedented halogen atom transfer from alkyl iodide to pentacarbonylmanganese radicals formed on photolysis of Mn 2 (CO) 10 . 14 The synthetic utility of these reactions is enhanced by their functional group tolerance; numerous examples illustrate compatibility with free hydroxyls, esters, silyl ethers, and alkyl chlorides.…”