JACS of Newhouse group: Benzyl dehydrogenation of electron deficient Heterocyclic Aromatic Hydrocarbons Catalyzed by aryl nickel

Dehydrogenation is a kind of important reaction, which can transform inert and low value alkanes into alkenes with high activity and added value Alkenes can also be used to transform into higher value chemical products One of the most important reactions in industry is the conversion of ethylbenzene to styrene for the preparation of polystyrene Global petrochemical enterprises produce one million tons of styrene every year, mainly using high temperature steam and k-fe2o3 heterogeneous catalyst （ Figure1A ）。 2-alkenyl heterocyclic aromatic hydrocarbons exist in a large number of FDA approved drug molecules, and they also act as precursors of olefin addition and polymerization (Figure 2C) Therefore, it is very important to develop a general and efficient method to introduce double bonds into the ortho position of heterocyclic aromatics Recently, the team of Timothy R Newhouse, Yale University, reported the benzyl dehydrogenation of electron deficient heterocyclic aromatics catalyzed by nickel, which is a β - hydrogen elimination process promoted by aryl oxidants The reaction has excellent site selectivity and is suitable for eight types of electron deficient heterocyclic aromatic hydrocarbons The results were recently published in J am Chem SOC (DOI: 10.1021 / JACS 9b12706) (photo source: J am Chem SOC.) firstly, the author used diphenylpyridine (1a) as the model substrate and Zn (TMP) 2 as the base to investigate the conditions (Table 1) According to the conclusion that allyl oxidants can promote the elimination of β - hydrogen of carbonyl compounds, which was reported by the research group in the early stage, the effect of oxidants was mainly investigated in this reaction The final results showed that 2-bromo-5-methylthiophene was the best oxidant and the yield of product 2A could reach 70% (photo source: J am Chem SOC.) after determining the best oxidant, the author inspected the ligands and additives (Table 2) Excessive TBAI can increase the selectivity of the reaction by inhibiting the formation of by-products PME 3, a phosphonic ligand with small steric hindrance and electron rich, is superior to that with large steric hindrance and electron deficient, such as P (n-Bu) 3, P (t-Bu) 3 and PCY 3 The effect of other ligands, such as bisoxazoline and bipyridine, was inferior to PME 3 (photo source: J am Chem SOC.) then, the author investigated the range of substrates (Table 3) For 2-phenylpyridine substrate, the reaction is compatible with electron donor (- me, - OME) and electron acceptor (- CN, - F, - CF 3) The inert substrate (1H - 1K) can also react, and the long-chain alkane side chain and cyclopropane substituent can be compatible The reaction was suitable for α, α - disubstituted (1m) and β, β - disubstituted (1n) substrates, but the selectivity of e-type decreased For different types of heterocyclic aromatic substrates, such as quinoline (1o-1q), pyrazine (1t, 1U), quinoxaline (1V), pyrimidine (1W, 1x), pyridazine (1y-1aa), triazine (1ab, 1Ac), the yield can be above medium Some functional groups are also compatible, such as N-Boc (1U), n-phth (1x), - OTBs (1AA) Substrate 1Ac has two nitrogen atom guiding groups, so it gives a double dehydrogenation product (photo source: J am Chem SOC.) next, the author conducted some mechanism verification experiments (Figure 2) Firstly, the dehydrogenation and deproton experiments (Figure 2a) were carried out on the substrate 1t At 20 min, the yield of the dehydrogenation product 2T was 42%, while that of the deproton product was only 2% When the reaction time was extended to 6 h, the yield was 83% at 2T and 36% at 1t - α d 1 This result shows that the formed Benzylzinc species are consumed by nickel catalytic cycle in the reaction In the KIE experiment, the KIE given by the intramolecular competition experiment is 2.8, while the KIE given by the intermolecular competition experiment is lower, which is 1.4 Based on the above experimental results, the elimination of β - hydrogen and reduction are not critical steps (photo source: J am Chem SOC.) finally, the author gives a possible catalytic cycle (Figure 3) Firstly, the oxidant ox 11 was oxidized by nickel to form intermediate B, which was converted to intermediate d by metallization with Benzylzinc species C; then, dehydrogenation product 2 and thiophene-ni-h species E were given by β - hydrogen elimination of D, and low-cost nickel species a was given by reduction elimination of e to complete the catalytic cycle (photo source: J am Chem SOC.) Summary: Timothy R Newhouse team reported the benzyl dehydrogenation of electron deficient Heterocyclic Aromatic Hydrocarbons Catalyzed by nickel, which uses ligands and oxidants to promote the β - hydrogen elimination process This method has excellent functional group compatibility and site selectivity, which provides an efficient and convenient method for the synthesis of 2-alkenyl heterocyclic aromatic compounds.