Halide and Oxidant Free Alkyl Heck-Coupling Reactions

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Feb 11, 2019

  The transition-metal-catalyzed Heck reaction (2010 Nobel Prize) has been established as a powerful tool for the cross-couplings of organic halides with olefins. However, the hazardous halide wastes produced may cause severe environmental concerns. Oxidative Heck-type coupling with organometallics or arenes as nucleophiles provides an alternative pathway. However, the examples reported so far were mostly restricted to the alkenylations of aromatics, and stoichiometric amounts of extra or internal oxidant were inevitably utilized. Although there are very few examples of dehydrogenative Heck couplings in absence of oxidants, the scope was limited to C(sp2)-C(sp2) bond formations. By comparison, Heck couplings involving C(sp2)-C(sp3) bond formations are much more challenging, and the oxidant-free, direct generation of H2 from alkyl Heck-type reaction is unprecedented and remains a highly formidable task. The primary motivation of this project was to develop a sustainable catalytic system for the direct dehydrogenative coupling reaction.

   To explore new chemical reactivity for sustainable syntheses and transformations is the central goal of C.-J Li’s lab. As is well known, the first Cross-Dehydrogenative Coupling (CDC) of two different C-H bonds was reported by our group (J. Am. Chem. Soc. 2004, 126, 11810). Since then, a myriad of efforts and contributions have been made by our group and many others in this rapidly growing field (Acc. Chem. Res. 2009, 42, 335; Angew. Chem. Int. Ed. 2014, 53, 74). Considering these achievements and inspired by our recent work in which hydrazones acted as novel carbanion equivalents instead of organometallic reagents in the catalytic nucleophilic addition (Nat. Chem. 2017, 9, 374), I wondered that if the direct H2 evolution was feasible with hydrazone as the nucleophile in the CDC reactions? Towards this idea, we selected Heck coupling as the proof-of-concept to test our hypothesis.

  After many trials, we are glad to find that this hypothesis becomes a reality under a simple nickel catalyst system with oxidant-free conditions, and H2 formation was confirmed by GC with a TCD detector. The innovation of this strategy is that umpolung aldehydes as novel alkyl electrophiles undergo Heck-type coupling reactions, liberating H2, N2 and H2O as the side products. High efficiency, excellent regioselectivity, broad substrate scope and great functional group compatibility revealed the powerfulness and versatility of this protocol. Due to the presence of Ni-H species, the allylic isomerization was a challenge, but could be controlled with the aid of neighboring oxygen atom coordination.

  The developing strategies towards the late-functionalization of complex natural products and pharmaceutical molecules is an important topic in Li Group. To this end, a series of biologically active molecules such as alkaloid, amino acid, vitamin and steroid were tested by this protocol and all worked efficiently, leaving the delicate functional groups (ketone, ester and amide) intact. We anticipate that this “oxidant free and H2 evolution” conception may provide a new perspective in the cross-coupling field and stimulate the chemists to further expand this sustainable philosophy to other areas.

  We would like to express our cordial gratitude to the referees, who gave us instructive and critical comments on the synthetic applications and mechanistic studies. These helpful suggestions have improved the manuscript and made the synthetic methodology stronger.

  Our research has now been published in Nature Communications  https://www.nature.com/articles/s41467-019-08631-1

Go to the profile of Leiyang Lv

Leiyang Lv

Postdoc, McGill University

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