Green chem.: Professor Zhu Chunyin group of Jiangsu University uses hydrazine hydrate as reducing agent to realize the green coupling of aryl halides

The author of the paper: Professor Zhu Chunyin's group coupling reaction can effectively realize the connection of two molecular fragments, which has a wide range of applications in materials, analysis, medicine and other fields But for a long time, this kind of reaction often needs precious metals as catalysts, and the reaction conditions are harsh, sensitive to air and water, and the experimental operation requirements are high Some reactions will be accompanied by the discharge of inorganic salt waste, which will bring pollution to the environment Recently, Professor Zhu Chunyin's research group of Jiangsu University used cheap and easily available hydrazine hydrate as reducing agent and palladium acetate as catalyst as low as 1% dosage to realize the coupling of aryl halides, providing an efficient green way for the synthesis of biaryl compounds The experimental operation of this method is simple, and there is no need to isolate air and water The by-product of hydrazine reaction is nitrogen and water, which reduces the discharge of waste materials and conforms to the concept of green synthesis The related achievements were published in green chem (DOI: 10.1039 / c8gc03862g) under the title of "living free palladium catalyzed Ullmann biological synthesis: 'Household' reactions and mil reaction conditions" At first, the author used 1-chloro-4-iodobenzene 1F as the model substrate to optimize the reaction conditions (Table 1), and selected a series of solvents, additives, alkali and reducing agent dosage Under the condition of PD (OAC) 2 (20 mol%) as catalyst, hydrazine hydrate (2.0 equivalent) as reducing agent and DMSO as solvent, the yield of biaryl compound 2F (entry 1) was 86% after the reaction of substrate at room temperature for 2 hours The same coupling products can also be produced with DMF as solvent, but the yield is decreased (entry 2) When the mixture of DMF and DMSO (V / V, 3:1) was used as solvent, the yield of the product was significantly increased (entries 12-13) After that, the author added K3PO4 on the basis of the above conditions, and found that 2F (entry 14) could be obtained in 86% yield after 6 hours using only 2.5 mol% of PD (OAC) 2 The author further reduced the dosage of PD (OAC) 2 to 1.0mol%, and the reaction could be completed in 10 hours, and 2F (entry 15) was obtained in 82% yield Finally, the amount of hydrazine hydrate was increased to 4.0 equivalent, and the yield reached 87% (entry 16) (source: Green chem.) then, under the optimal reaction conditions, the author explored the range of reaction substrate (Table 2) All kinds of aryl / heteroaryl iodides can react smoothly to get biaryl compounds in medium to good yields The reaction is sensitive to steric hindrance, the substituent substrate shows good activity, and the biaryl compound 2C can be obtained in good yield; however, when steric hindrance is applied in the neighborhood, the reaction activity drops sharply, and the required coupling product 2D is not separated under the current conditions The electronic effect of substituents has little effect on the reaction efficiency The aryl iodine with electron donor or electron acceptor on the aromatic ring can be converted into corresponding biaryl compounds (2B, 2h vs 2I, 2K) in good yield It is worth noting that heteroaryl iodides such as 2-iodopyridine can also react smoothly under the current conditions, and bipyridine 2J can be obtained with excellent yield (89%) (source: Green chem.) for ortho substituted iodobenzene, the author observed the production of reduction products In order to study the effect of spatial effect, the author has carried out a series of studies on ortho substituted iodobenzene (Table 3) Under standard conditions, all ortho substituted aryl iodides (1L - 1o) are reduced to simple aromatic compounds in good yields The substrate 1p was simply reduced instead of intramolecular coupling However, the 1q structure similar to the substrate 1p did not react at all At the same time, there was no coupling or reduction between 2-iodothiophen1r and 1-iodonanaphthalene 1s (source: Green chem.), the author used two different kinds of iodobenzene (1:1 mol) to study cross coupling under standard conditions (Table 4) In the reaction of aryl iodide with weak electron donor group and strong electron donor group (e.g - OME), the author mainly observed the self coupling product (entries 1-4) The reaction of aryl iodides with strong electron absorbing groups (- CN, - F, - CF 3) tends to produce more cross coupling products (entries 6-9) Among them, the reaction of 1-iodo-4-methoxybenzene with 1-fluoro-4-iodobenzene has the highest cross coupling selectivity The author isolated three kinds of biaryl compounds from them, with a total yield of 90%, of which 56% are asymmetric biaryl compounds (entry6) The author tried to improve the cross coupling selectivity by increasing the ratio of a substrate (entries 11-14) The results showed that increasing the ratio of 1-fluoro-4-iodobenzene could improve the cross coupling selectivity When 5.0 equivalent of 1-fluoro-4-iodobenzene is used, the proportion of asymmetric / symmetric biaryl compounds can be increased to 78:22 (entry 14) (source: Green chem.) further, the author tried to introduce ligands and additives into the reaction to improve the selectivity (Table 5), but found that phosphine ligands including PPh3, DPPP and DPPE could inhibit the reaction In the presence of PPh3, the conversion of iodobenzene was only less than 10%, while in the presence of DPPP or DPPE, there was no reaction at all (entries 1-3 ) In addition, we also tried to use 2,2-BIPYRIDINE and TBAC as ligands / additives, but they did not significantly improve the selectivity (entries 4-5) (source: Green chem.) in order to further understand the reaction mechanism, especially the active source of palladium catalyst, the author further studied the reaction, and found that some fine dark gray particles precipitated during the reaction process, and the precipitate can promote the coupling reaction of aryl iodides again The authors speculate that these dark gray particles are palladium nanoparticles (pdnps) In order to further confirm this conjecture, Pd (OAC) 2 was treated with excessive hydrazine hydrate in the mixture of DMSO and DMF (1:3) to prepare pdnps in advance The precipitates were filtered and washed to obtain dark gray powder Pdnps (Figure 1) with size of 50-100 nm was observed in SEM test (source: Green chem.) in addition, this pre formed pdnps showed good activity (scheme 2) in the self coupling reaction of 4-iodobenzonitrile It is worth noting that pdnps can be recovered in good yield and keep its catalytic activity after 3 cycles (source: Green chem.) based on these experimental observations, the author proposed a possible reaction mechanism (scheme 3) In the presence of hydrazine hydrate, Pd (OAC) 2 is reduced to PD 0 to initiate the reaction, and then the aryl iodide is oxidized and added to PD 0 to form PD II complex 6 The intermediate 7 and PDI 2 are produced by the transition metallization reaction between two PD II complexes 6 Hydrazine hydrate reduced PDI 2 to PD 0, while intermediate 7 produced coupling products through reduction elimination, and PD 0 which can re enter the catalytic cycle (source: Green chem.) in a word, the author developed a new method of palladium catalyzed synthesis of biaryl compounds with hydrazine hydrate as reducing agent The reaction is suitable for both electron rich and electron deficient aryl iodides and heteroaryl iodides, and a variety of biaryl compounds are obtained in good yields The reaction has the advantages of simple operation, easy access to raw materials, wide range of substrate application and application to gram scale synthesis.