The biaryl skeleton is highly valuable in modern chemistry and industry. Transition-metal catalyzed couplings of aryl halides or arenes with aryl organometallics, and direct reductive coupling of two aryl halides, are the predominant methods to synthesize biaryls. However, stoichiometric amounts of metals were inevitably required for these reactions, either in the pre-generation of organometallic reagents or acting as reductant in situ. The primary motivation of our project was to develop a more sustainable catalytic system for biaryl synthesis.
C.-J Li’s lab has long been committed to exploring new chemical reactivity for sustainable syntheses and transformations. Inspired by the earlier work from our group that hydrazone acting as novel carbanion equivalent instead of organometallic reagent in the catalytic nucleophilic addition (Nat. Chem. 2017, 9, 374), I came up with a fantastic idea that if simple hydrazine could act as metal surrogate in chemical transformations? I was not sure if this proposal would get approval of Prof. Li because it sounded like the story in the Arabian Nights. However, Prof. Li told me that you should be the first to eat crabs, and you never know unless you try.
As is well known, in the presence of stoichiometric amount of metal reductant such as Zn, Mn and Mg, the Ullmann reaction displays powerful ability to couple aryl electrophiles. We then selected the Ullmann coupling as the proof-of-concept to test our hypothesis. Initially, the competing hydro-dehalogenation reaction occurred predominantly. After optimizing the catalyst, ligand, base and solvent, this strategy enabled efficient formation of biaryl structures with N2H4 as a traceless reductant. (Hetero) aryl/vinyl triflate, tosylate, mesylate and halide are all applicable. N2 and H2 are generated as readily escapable side products, making the coupling reactions dramatically clean and easy to handle. Theoretically, one molecule of hydrazine can provide at least 2 electrons (H2 was detected by GC), thus explaining that 0.5 equiv of hydrazine is able to reduce 1.0 equiv of aryl electrophile to give the corresponding coupling product.
The cross-Ullmann couplings of aryl electrophiles and /or alkyl electrophiles were also realized with the excess of one substrate. As demonstrated by Prof. Weix, the multi-metallic synergistic catalysis with N2H4 as the reductant may be a good solution. In addition, other coupling reactions are also envisioned and are undergoing in our lab
As the late-stage functionalization is an important topic in Li Group, we also evaluated the applications of this methodology in the modification of complex natural products and drug molecules. Both homo- and cross-couplings of a series of alkaloids, amino acids and steroids worked efficiently with the fragile functional groups (ketone, ester and amide) intact.
We would like to express our cordial gratitude to the referees, who gave us instructive and critical comments on the mechanistic studies. These helpful suggestions improve the manuscript and enable the synthetic methodology stronger.
Our research has now been published in Nature Communications https://www.nature.com/articles/s41467-018-07198-7