Iron‐Catalysed Reductive Cross‐Coupling of Alkenes

Radical stuff: Iron-catalyzed alkene hydrofunctionalization has been reported by a number of groups using the reaction of unactivated alkenes with sodium borohydride or phenylsilane to give alkyl radical intermediates. Reaction with a range of radical traps has been applied to the formation of carbon–carbon and carbon–heteroatom bonds and used recently for reductive cross-coupling of alkenes. EWG=Electron-withdrawing group. The construction of carbon–carbon bonds is fundamental to chemical synthesis. With ever-growing global chemical demand and energy consumption, the development of efficient, energy saving and environmentally benign synthetic processes is paramount. Cross-coupling reactions are ubiquitous for carbon–carbon bond formation, however, the use of precious or toxic transition metal catalysts, pre-functionalisation of coupling partners and the removal of inorganic waste effect the sustainability of these reactions. Olefin metathesis is a powerful reaction due, in part, to the wide availability of alkenes and alkynes and the relatively small amount of waste material produced, however, precious and semi-precious transition metal catalysts are commonly used. The direct coupling of alkenes by using an inexpensive, bench-stable and environmentally-benign catalyst is, therefore, an attractive reaction. Iron offers significant advantages as a catalyst due to its low toxicity, low cost, natural abundance and sustainable long-term availability. Baran and co-workers have recently reported an iron-catalysed reductive cross-coupling of alkenes.1 Iron-catalysed reductive radical formation was used to mediate the cross-coupling of primary, 1,1-disubstituted and tertiary alkenes with electron-deficient alkenes. Iron-catalysed reductive formation of alkyl radicals, from alkenes and a hydrogen source, has been used by a number of groups for the hydrofunctionalisation of alkenes (Scheme 1). Sodium borohydride or phenylsilane were most commonly used as the hydrogen source. Iron-catalysed reductive alkyl radical formation and trapping. Biomimetic iron porphyrin complexes were first used by Okamoto, Hirobe and Kano for the hydration of alkenes to give alcohols, by using atmospheric oxygen and sodium borohydride (Scheme 2).2 Iron(III) alkyl species, formed by addition of the alkene into an iron–hydride species, have been suggested as key intermediates in these reactions.3a It was proposed that the reactivity of these intermediates could be considered analogous to that of an alkyl radical. Kano found that under anaerobic conditions the same iron(III) porphyrin complexes catalysed the reduction of styrene derivatives with sodium borohydride in benzene–ethanol solutions to give a mixture of products from both formal hydrogenation and reductive homo-coupling.3 An iron(II) alkyl porphyrin ate complex was suggested as a carbanion equivalent leading to the formal hydrogenation products, whereas the reductive homo-coupling products were proposed to arise from radical dimerisation of an iron(III) alkyl intermediate. Kano found subsequently that hydrothiolation could be achieved by the addition of dialkyl or diaryl disulfides under anaerobic conditions.4 Recently, the nitrosation of styrene derivatives to give oximes was demonstrated by using 1 mol % iron catalyst, sodium borohydride and tert-butyl nitrite as the nitrogen monoxide source.5 Once again, an iron(III) alkyl species was proposed as an alkyl radical equivalent in the reaction, which was trapped by reaction with tert-butyl nitrite. Mukaiyama had previously reported the nitrosation of alkenes by using phenylsilane as the hydrogen source, rather than sodium borohydride, however in this case alkyl nitroso dimers were predominantly formed.6 Iron-catalysed and mediated hydrofunctionalisation of alkenes. By using iron(III) oxalate and sodium borohydride, Boger developed and extended the previous methodologies7 to produce a general system for the hydrofunctionalisation of alkenes with a range of radical traps (Scheme 2).8 Phenylsilane could also be used as the hydrogen source, however, increased reaction times were required. Carbon–heteroatom and carbon–carbon bond formation occurred at the most substituted alkene carbon, consistent with the stabilisation of a radical intermediate. Good to excellent yields were obtained with a number of radical traps. The use of diethyl diallylmalonate gave only the ring-closed products, consistent with an alkyl radical intermediate. The methodology was applied elegantly to the synthesis of C20′ vinblastine analogues through selective late-stage alkene functionalisation. A number of methodologies that employ stoichiometric and sub-stoichiometric iron salts have been developed to catalyse the intramolecular addition of alkyl radicals to pendant alkenes to give carbo- and heterocycles (Scheme 3).9 Tu developed the first example of an iron-catalysed intermolecular carbon–carbon coupling reaction between primary alcohols and styrene derivatives via an alkyl radical intermediate.10 Tertiary benzylic alcohols could be used in place of the styrene derivatives, presumably dehydrating under the reaction conditions. The reaction was proposed to proceed by iron-initiated carbon–hydrogen bond cleavage, adjacent to the hydroxyl group, to give an iron(IV) hydride–alkyl radical pair. Alkyl radical addition to the alkene and, finally, hydrogen abstraction from the iron(IV) hydride gave the cross-coupled products. Iron-catalysed and mediated radical additions to alkenes. EWG=Electron-withdrawing group. Ts=Tosyl. Baran combined these two areas of iron-catalysed radical chemistry to produce an efficient iron-catalysed reductive cross-coupling between unactivated alkenes and electron-deficient alkenes (Scheme 4).1 Reaction of an iron salt and either sodium borohydride or phenylsilane and an alkene was used to generate a stabilised alkyl radical, which underwent conjugate addition to an intra- or intermolecular Michael acceptor to give the cross-coupled product. Reactions were generally complete within 1 h with 20–100 mol % iron(III) acetylacetonate and 150–250 mol % phenylsilane. Although slight optimisation of solvent composition was required for some examples, in general, a combination of ethanol, ethylene glycol and 1,2-dichloroethane gave the cross-coupled products in good to excellent yields. The reaction tolerated the presence of oxygen and water, demonstrating the simplicity and practicality of the methodology. Interestingly, the reaction also proceeded under anaerobic conditions, indicating that oxygen was not responsible for catalyst reoxidation. Coupling was achieved by using unfunctionalised and functionalised alkenes (with N-tert-butoxycarbonyl or tert-butyldimethylsilyl ether groups) with α,β-unsaturated systems, including ketone, ester, aldehyde, amide, nitrile and sulfone functionalities. Both intra- and intermolecular couplings (with an excess of one coupling partner) gave products in equally high yield, however, no selectivity was demonstrated for systems bearing multiple alkenes or α,β-unsaturated systems. In all cases, carbon–carbon bond formation occurred regioselectively at the most substituted alkene carbon, consistent with alkyl radical stabilisation. Significantly, no homo-coupling of the proposed intermediate alkyl radical species was observed, however competitive alkene reduction was reported in some cases. The potential for rapid construction of terpenoid-like structures was demonstrated by intramolecular reductive cross-coupling to give complex bi- and tricyclic structures, including those with vicinal quaternary centres. Iron-catalysed reductive cross-coupling of alkenes. TBS=tert-Butyldimethylsilyl. In conclusion, Baran has made a valuable and useful contribution to iron-catalysed cross-coupling and carbon–carbon bond forming methodology. The reductive formation of alkyl radicals from alkenes and phenylsilane was successfully applied in conjugate addition to electron-deficient alkenes to give cross-coupled products. The process represents a highly atom-economical approach to carbon–carbon bond formation with inexpensive reagents insensitive to air and moisture.