Nat. Chem.: Dong guangbin's research group realizes the selective functionalization of complementary sites of aromatics by palladium / norbornene

The functionalization of aromatics site selectivity plays an important role in the study of drugs, pesticides and materials In general, aromatics functionalization is realized by electrophilic substitution and further standard conversion of aromatics; therefore, electrophilic substitution tends to occur in the more electron rich and accessible positions of aromatics (Fig 1a) Whether complementary and full site selective functionalization (such as the Antiposition of EWG or the interposition of EDG) can be realized in the position unfavorable to the electrophilic substitution of aromatics has attracted extensive attention of researchers Palladium / norbornene (Pd / NBE) Co Catalysis (i.e catelani type reaction) can solve the above challenges Taking the key aryl norbornene ring target as the intermediate, the electrophilic and nucleophilic reagents can produce coupling reaction under the action of reducing agent at the same time, so as to realize the dual functionalization of ortho and standard or single ortho functionalization However, due to the inherent "ortho inhibition" in Pd / NBE catalytic system, the non substituted halogenated aromatic hydrocarbons usually can not obtain a single ortho functionalization, but a complex mixture containing NBE by-products or bifunctions (Fig 1b) Recently, Dong guangbin's research group of the University of Chicago solved the above problems by using the new NBE "auxiliary factor" to realize the single orthofunctionalization of ortho unsubstituted aryl iodide By electrophilic halogenation and orthofunctionalization of aromatics, unconventional site selective functionalization of aromatics (such as EWG and EDG) and site selective C-H amination of natural products and drugs with complex biological activities (Fig 1c) can be realized Relevant articles were published on NAT Chem (DOI: 10.1038 / s41557-018-0074-z) under the title of "comprehensive site selectivity in arena functional enabling by overlapping the ortho constraint in palladium / norborn catalyst" (source: Nat Chem.) the research team of catelani showed that the "ortho inhibition" of Pd / NBE catalytic system originated from the second C-H metallization, which was easier than β - carbon elimination As shown in Figure 2, in the transition state of C-H metallization of conventional NBE, the newly installed electrophilic agent e must face the bridgehead position; on the contrary, in the transition state of β - carbon elimination, the aromatic ring plane must be almost perpendicular to the C-H bond of the bridgehead Therefore, the key to inhibit the second C-H metallization or promote the elimination of β - carbon is to control the orientation of aromatic groups in the transition state It is assumed that the steric hindrance between the Group R and the electron acceptor group (or between the R group and the palladium ligand) will lead to the instability of C-H metallization in the transition state, and promote the elimination of β - carbon by the orientation of the fixed aromatic ring (Fig 2b) (source: Nat Chem.) in order to confirm the above hypothesis, the author chose ortho amination / Heck reaction as the model reaction In the past, 2-iodotoluene can form 81% ortho amination products, but 3-iodotoluene and 4-iodotoluene can not get mono functional products (Fig 3) Therefore, the feasibility of ortho amination was investigated with 3-iodotoluene (1a) as the starting substrate and benzoyloxyamine 2A as the limiting reagent The author thinks that the size and position of substituents are key Increasing the steric hindrance of NBE can promote the elimination of β - carbon, but it can also reduce its binding affinity and lead to the formation of heck by-product (4a ') A variety of NBE (Table 1, entry 1) were prepared and screened It was found that bridgehead (n2-n5) can effectively obtain the target monoamination product (4a) even with alkyl substitution NBE, and n-heptyl substitution N3 is the best It was found that, although other ligands such as 1,2-bis (diphenylphosphine) ethane (DPPE) and N-heterocyclic carbene can also promote the transformation, the yield of 4A was the best when ruphos was used as the ligand Then, palladium, phosphine ligands and NBE were proved to be the key reactions (entries 2-4) The author continued to optimize the reaction conditions and found that [PD (allyl) Cl] 2 is more efficient than PD (OAC) 2 (entry 5); compared with cesium carbonate, using potassium carbonate as base greatly reduces the yield (entry 7) (source: Nat Chem.) under the optimal reaction conditions, the author first investigated the application range of iodoaromatic hydrocarbons (Table 2) The aryl iodine substituted by the electron donor (4a-4g) and the electron acceptor (4h-4j) are both effective coupling ligands; the meso and para disubstituted substrates (4k-4m) are also compatible Heterocyclic groups such as carbazole, quinoline, thiophene and naphthalene iodide (4O - 4R) can also react smoothly Next, the author investigated the substrate range of other amines and alkenes A variety of benzoyloxyamines (such as protected piperidine, piperidine and BOC protected piperazine (4s-4x)) can be successfully reacted, and the bisubstituted products can be obtained in good yield In addition, the coupling reaction between methyl acrylate and n-butyl acrylate can also be carried out smoothly It is gratifying to note that the target amination products (4AB and 4ac) are also obtained in good yields from the ortho unsubstituted aryl iodides in complex molecules such as estrone and loratadine (source: Nat Chem.) in addition, in order to emphasize the universality of the strategy, the author also investigated the reaction range of different quenching reagents in the standard In addition to heck coupling, hydrogen, aryl or alkynyl groups can be added to the standard by reaction with reducing agent (6a), Suzuki (6b) or Sonogashira (6c) quenching agent N3 cofactor can also be applied to the ortho acylation (8a-8f) and ortho arylation (10a-10f) of aromatics, which indicates that the reaction has a wide range of applications The feasibility of the reaction was examined by using para substituted aryl iodides The second C-H metallization is easier, which makes the reaction more challenging In order to further inhibit the second C-H metallization (Fig 2b), N8 with alkyl substitution on two bridgeheads was synthesized It is satisfactory that the target monofunctionalized product (12a) can be obtained in 55% yield by using N8 as an auxiliary factor, and its mono / di selectivity is greater than 20:1 (FIG 4A) This is the first example that Pd / NBE catalyzes o-and m-unsubstituted aryl iodides to obtain monofunctional products The corresponding products (12b and 12C) can still be obtained by substituting iodinated aromatics with EDG or EWG (source: Nat Chem.) finally, the author introduced amino functional groups (Fig 5) into the para (15a-15c) and the ortho (15d-15f) of the electron acceptor group of aromatics through continuous electrophilic iodization and ortho functionalization The practicability of this method has been further proved in the late site selective derivation of complex molecules (19, 21, 23) (source: Nat Chem.) conclusion: Dong guangbin's research group has developed a new type of NBE cofactor that can overcome the ortho limit in Pd / NBE catalysis and realize the selective functionalization of arene complementary sites Through continuous C-H iodization and ortho functionalization, this strategy can introduce functional groups at positions that are not conducive to the electrophilic substitution of aryl groups, which provides a unique method for the selection of control sites.