JACS: Dong guangbin's research group of the University of Chicago realizes the ortho dual functionalization of thiophene by palladium / norbornene

Polysubstituted heteroaromatic hydrocarbons are widely found in drugs, agricultural chemicals and organic materials (Figure 1) The functionalization of heteroaromatics can be effectively realized by directly regioselective conversion of inactive C-H bonds into new functional groups (FG) At present, a FG can be selectively introduced into heteroaromatics without the aid of a guiding group (DG) However, at the same time, the introduction of two different FGS is still challenging (photo source: J am Chem SOC.) palladium / norbornene (Pd / NBE) Co Catalysis (i.e catelani type reaction) is a common method for the ortho dual functionalization of aromatics At first, catelani and lautens et al Used arylhalides as substrates to realize both electrophilic and nucleophilic coupling with aromatics (scheme 1a) In 2015, Yu Jinquan and Dong guangbin reported the scheme 1b of palladization oriented aromatics Recently, the research group of residual gold weight has developed the electron rich arylation of alkoxy aromatics However, the C-H initiated Pd / NBE catalyzed ortho dual functionalization of aromatics has not been reported Recently, Dong guangbin group of the University of Chicago realized the double C-H functionalization (scheme1c) of thiophene at C4 and C5 positions by using a unique catalytic system through Pd / NBE catalyst, which was recently published in J am Chem SOC (DOI: 10.1021 / JACS 9b10857) (photo source: the C5 (or C2) site of J am Chem SOC.) thiophene is the most electron rich Although a variety of direct C-H metallization methods have been developed, due to the lack of ortho substituents to promote the removal of NBE and the ability of sulfur coordination to hinder the palladization of C4 and NBE (scheme 2), it is still of great significance to directly combine C5 palladization with Pd / NBE catalysis The authors hypothesized that the key to solve the problem of sulfur coordination is to use weak π - acid ligands to promote its decarboxylation from thiophene sulfur without inhibiting the process of C-H palladization and catelani In addition, the use of larger volume of NBE is beneficial to promote the removal of NBE through β - carbon removal (photo source: J am Chem SOC.) in order to test the above hypothesis, the author investigated the ortho arylation / standard Heck reaction (Table 1) with 2-butyl thiophene (1a) as the model substrate In the previous arylation reaction, AsP3 is superior to phosphine and phosphite ligands; after systematic optimization, c4,5-difunctional product (4a) can be obtained in 82% yield In the absence of PD or NBE, the expected product was not obtained The results show that the NBE (N1) substituted by C2 methylamide is the most effective, and other substituted NBE are not ideal Bifunctionalization requires a stoichiometric oxidant to regenerate PD (II) catalyst Therefore, BQ and agoac are very important for the reaction BQ may be used as redox active ligand to promote the rapid oxidation of PD (0) to PD (II), while agoac assists the activation of C-I bond by forming AgI At lower concentration, the reaction efficiency is lower, and Hoac is beneficial to the reaction When the equimolar substrates 1a and 2a are used, the product 4A can be obtained in good yield In addition, the reaction can be carried out with relatively low reaction temperature (65 ℃) when exposed to air (photo source: J am Chem SOC.) after determining the optimal reaction conditions, the author investigated the range of thiophene substrate (Table 2): thiophene with various substituents (including alkyl, electron rich and electron deficient aryl substituents) at C2 site is a suitable substrate for ortho bifunctional For 4G, C-H functionalization occurs on thiophene rather than on electron rich alkoxyaromatics The reaction can tolerate a variety of groups, including methoxy, benzyl and methylsilyl protected primary alcohols and esters Substrates containing halogens such as 2-chlorine and 2-Bromothiophene are also reactive and can be used for further functionalization The disubstituted thiophene at C2 and C3 sites is also an effective substrate, and can be prepared by conventional methods In addition, the reaction can also tolerate internal alkynes and be used to prepare tetrasubstituted thiophene (photo source: J am Chem SOC.) next, the author examined the range of aryl iodides and olefins (Table 3) Aryl iodides containing ortho electron acceptors are the most effective, and esters, amides, ketones and nitro substituted aryl iodides can also be used as effective electrophilic reagents Another kind of aryl iodide, which is not substituted by ortho electron withdrawing group, can also participate in the reaction; the reaction efficiency of other aryl iodides, especially electron rich ones, is very low In addition to methyl acrylate, other Michael receptors such as conjugated esters, amides and ketones, and electrically neutral styrene are also good coupling mates for C5 functionalization (photo source: J am Chem SOC.) this method can be applied to derivatization of complex bioactive compounds containing thiophene (Table 4) Vitamin E, estrone, hexahydro-1,4-diazo-l-proline adduct, clopidogrel and the derivatives of duloxetine protected by BOC can all obtain bifunctional products in medium to good yields In addition, the reaction conditions are mild and suitable for mass synthesis (eq.1) (photo source: J am Chem SOC.) in addition to thiophene, this method is also suitable for simple furan substrate When 2-butylfuran 1t is used as the substrate, the trisubstituted product 8 (eq.2) can be obtained in 30% yield In addition, when there is no 3a in the reaction system, the direct C4 aromatization (eq.3) can be realized by using excessive Hoac (photo source: J am Chem SOC.) there are two possible pathways for this reaction: "coupled" bifunctionalization (path a) or step-by-step C4 / C5 functionalization (path B) It can be seen from the kinetic curve of the model reaction (Fig 2) that the bifunctional product (4a) is formed immediately at the beginning of the reaction, and there is no accumulation of C4 intermediate (9a) The competitive experiments further showed that the direct bifunctionalization was more advantageous than the C5 alkylation of 9A Both of the above results support the "coupled" bifunctional pathway (path a) (photo source: J am Chem SOC.) conclusion: Dong guangbin's research group has developed a new method of using Pd / NBE The method of CO catalysis to realize thiophene ortho dual functionalization has excellent tolerance of electron absorbing group and excellent site and region selectivity Its mild and stable reaction conditions make it have a broad prospect in the preparation of complex polysubstituted thiophene and late functionalization of bioactive compounds.