During the development of a total synthesis of (–)-acutumine (1), the reduction of the alkenyl chloride 2 to the desired natural product 1 presented a major difficulty.1 The facile hydrodehalogenation reaction we observed, to generate (–)-dechloroacutumine (1a), highlighted the absence of general methods to affect the selective reduction of alkenyl halides to the corresponding alkyl halides.

acutumine reduction.jpg

We recognized that a hydrogen atom transfer pathway,2 which avoids the generation of discrete organometallic intermediates, may provide a means to circumvent hydrodehalogenation. We developed a method to achieve the reduction of alkenyl halides that is based on related alkene hydrofunctionalization reactions which proceed by cobalt-, manganese-, or iron-mediated hydrogen atom transfer.3 The method employs cobalt bis(acetylacetonate) in stoichiometric or substoichiometric quantities, and 1,4-cyclohexadiene (1,4-CHD) and triethylsilane as hydrogen atom sources. Among a broad range of alkenyl halides surveyed (including geminal dihalides and those possessing redox-sensitive functional groups) hydrodehalogenation products were not observed.4

When a similar system was applied to unfunctionalized alkenes, we observed that the relative rates of reduction of several alkene and alkene–alkyne pairs were distinct from classical hydrogenation protocols.5 Traditional hydrogenation catalysts typically favor the reduction of less-hindered or more-strained alkenes, while the hydrogen atom transfer reduction we developed preferentially reduces alkenes that form the more stable alkyl radical intermediate.

We also extended these studies toward the first hydrobromination, hydroiodination, and hydroselenation reactions that proceed by hydrogen atom transfer.

Control experiments revealed that when the hydrogen atom donor 1,4-CHD was omitted from the reduction process, the radical intermediate underwent oxidation, ultimately providing a ketone or ester.4 We pursued this lead and reported the formal hydrolysis of heteroatom-functionalized alkenes to generate the corresponding ketones and esters.6

While the addition of nucleophilic carbon-centered radicals formed under HAT conditions to electron-deficient alkenes has been developed,7 the intermolecular hydro-(hetero)arylation of unfunctionalized alkenes via HAT was underdeveloped. After extensive experimentation, we discovered that N-methoxypyridinium methylsulfate salts are useful reagents to effect the formal hydropyridylation of alkenes under HAT conditions.8

We extended the substrate scope by first developing syntheses of a large pool of N-methoxyheteroarenium methylsulfate derivatives with varied functional groups and heteroarene cores.

We showed that the scope of this transformation is broad. We coupled 36 discreet heteroarenium salts with 38 different alkenes under neutral conditions at ambient temperature. Monoalkylation products were formed exclusively and only a single alkene addition regioisomer was detected. 9 We also observed synthetically useful and complementary site-selectivities in the addition of secondary and tertiary radicals to pyridine derivatives. More than 66 substrates were prepared. This chemistry connects HAT to alkenes with Minisci additions (addition of radicals to electron-deficient heteroarenes). 10

Substrate Scope.jpg

We are currently investigating the site-selective hydrofunctionalization of dienes, the hydroarylation of unactivated alkenes with novel arylation reagents, and methods for C(sp3)–C(sp3) coupling.


  1. King, S. M.; Calandra, N. A.; Herzon, S. B. "Total syntheses of (–)-acutumine and (–)-dechloroacutumine." Angew. Chem., Int. Ed. 2013, 52, 3642.

  2. For reviews, see: (a) Eisenberg, D. C.; Norton, J. R. "Hydrogen-atom transfer reactions of transition-metal hydrides." Isr. J. Chem. 1991, 31, 55. (b) Gansäuer, A.; Shi, L.; Otte, M.; Huth, I.; Rosales, A.; Sancho-Sanz, I.; Padial, N.; Oltra, J. E. Hydrogen Atom Donors: Recent Developments. In Radicals in Synthesis III; Heinrich, M., Gansäuer, A., Eds.; Springer Berlin Heidelberg: 2012; Vol. 320, pp 93.

  3. Crossley, S. W. M.; Obradors, C.; Martinez, R. M.; Shenvi, R. A. "Mn-, Fe-, and Co-Catalyzed radical hydrofunctionalizations of olefins." Chem. Rev. 2016, 116, 8912.

  4. King, S. M.; Ma, X.; Herzon, S. B. "A method for the selective hydrogenation of alkenyl halides to alkyl halides." J. Am. Chem. Soc. 2014, 136, 6884.

  5. Ma, X.; Herzon, S. B. "Non-classical selectivities in the reduction of alkenes by cobalt-mediated hydrogen atom transfer." Chem. Sci. 2015, 6, 6250.

  6. Ma, X.; Herzon, S. B. "Synthesis of ketones and esters from heteroatom-functionalized alkenes by cobalt-mediated hydrogen atom transfer." J. Org. Chem. 2016, 81, 8673.

  7. Lo, J. C.; Gui, J.; Yabe, Y.; Pan, C.-M.; Baran, P. S. "Functionalized olefin cross-coupling to construct carbon–carbon bonds." Nature 2014, 516, 343.

  8. Ma, X.; Herzon, S. B. "Intermolecular hydropyridylation of unactivated alkenes." J. Am. Chem. Soc. 2016, 138, 8718.

  9. Ma, X.; Dang, H.; Rose, J. A.; Rablen, P.; Herzon, S. B. "Hydroheteroarylation of unactivated alkenes using N-methoxyheteroarenium salts." J. Am. Chem. Soc. 2017, 139, 5998.

  10. Duncton, M. A. J. "Minisci reactions: Versatile CH-functionalizations for medicinal chemists." Med. Chem. Comm. 2011, 2, 1135.