The substitution reaction on the aromatic ring is one of the most widely used reactions in organic chemistry. However, due to the limitation of the reaction mechanism, these substitution reactions can often only proceed at specific positions on the benzene ring. For example, benzene rings containing electron-rich groups often undergo electrophilic substitution reactions at the ortho or para positions of the substituents; while electron-deficient heteroaromatic compounds often undergo nucleophilic substitution reactions at the ortho or para positions of the heteroatoms. In order to overcome these limitations, organic chemists often use rearrangement reactions to obtain products that cannot be obtained by substitution reactions. Although the classic rearrangement reactions (such as Smiles rearrangement, Claisen rearrangement, Bamberger rearrangement) have been widely used, these reactions can only rearrange part of the original substituents, so the net result of these rearrangement reactions is Change the original one substituent into two substituents. The rearrangement reaction that completely transfers the substituent from one position of the benzene ring to another is not common in organic chemistry. The most classic is the transalkylation reaction, that is, under the conditions of the Friedel-Crafts alkylation reaction, Rearrange the alkyl group on the alkylbenzene from one position to another. Although this reaction has gained some applications in the petrochemical field, it requires a strong Lewis acid, and the product is usually a mixture. The product of the reaction has poor predictability, so its application in the field of organic synthesis is very limited. Another famous example is the "halogen atom migration" reaction involving halogenated aromatic hydrocarbons. That is, under strong alkali conditions, halogen atoms can migrate from one carbon atom to another through a series of metal-halogen exchange reactions on the aromatic ring. Because of the practicality and predictability of this reaction, it is widely used in organic synthesis and even the total synthesis of natural products.
Although rearrangement reactions based on alkyl groups and halogens have been reported so far, no rearrangement reactions based on carbonyl functional groups have been reported. In this context, the research group of Professor Junichiro Yamaguchi from Waseda University in Japan reported a new palladium-catalyzed rearrangement reaction of ester functional groups on aromatic rings, which filled the gap. The researchers called this reaction "Ester Dance". "("Ester dance" reaction). Specifically, the ester group can be transferred from one carbon atom on the (hetero) aromatic ring to the adjacent carbon atom under the catalysis of palladium, thereby obtaining thermodynamically stable regioisomer products, and the conversion rate of the reaction is moderate to good . This work was recently published on Science Advances.
An important research direction of Professor Yamaguchi's group is the development of metal-catalyzed unconventional coupling reactions. When Yamaguchi was an associate professor in the Itami group of Nagoya University in Japan, he reported a series of unconventional coupling reactions based on hydrocarbon activation and carbonyl electrophiles. During the research on the decarbonylation of aryl esters, they found that under the catalysis of metal palladium, a small amount of ester groups on phenyl 1-naphthoate (1a) would rearrange from the C1 position to the C2 position to give benzene 2-naphthoate. Esters, although the yield is low (18%). Based on this unexpected discovery, they speculated that the rearrangement reaction may be carried out through the following tandem reaction:
1) The oxidative addition of palladium to the ester group C(O)─O bond,
2) Aryne-palladium complexes are produced after deprotonation and decarbonylation,
3) Re-insertion of carbonyl group after protonation;
4) Reduction and elimination.
Under the guidance of this hypothetical mechanism, they optimized the reaction conditions. Finally, they found that under the conditions of 10 mol% of the catalyst PdCl2, 20 mol% of the ligand dcypt, 0.5 equiv of the additive potassium carbonate and solvent meta-xylene at 150 ℃ for 24 h, the yield of the rearrangement product 2a was as high as 85% . The control reaction showed that in the absence of PdCl2, dcypt or potassium carbonate, the reaction could not take place at all. Although other palladium catalysts (such as PdBr2) can also catalyze the reaction, their activity is poor. Other metal catalysts (such as NiCl2) are completely inactive. The author also studied other electron-rich bidentate ligands (such as dcype, dcypbz), and the results showed that although they can drive the reaction, the effect is not as good as dcypt. In addition, when other bases were used instead of potassium carbonate, the reaction was completely inhibited, which suggests that the reaction may have undergone a deprotonation process assisted by the base. Further research on solvent effects showed that other high boiling point solvents (such as toluene, 1,4-dixoane, DMF) are not as effective as meta-xylene.
Under optimal conditions, the author evaluated the substrate range of the reaction. First, the author studied the functional group compatibility of the ester phenol moiety. The results showed ortho/meta/para tolyl groups (1b-1d), para/met anisole groups (1e and 1f), para/meta fluorophenyl groups (1g and 1h), and Both the para/met biphenyl groups (1i and 1j) are compatible with this reaction, and the target rearrangement product (2b-2j) is obtained with a moderate yield (42-71%). For benzoheterocyclic compounds, related rearrangement products can also be obtained (2k-2m). In general, due to the reversibility of the reaction, the conversion rate of the reaction is generally less than 90%. In addition to the target product, the reaction will be accompanied by the recovery of raw materials and the formation of by-product carboxylic acid (ester hydrolysis). Secondly, the author also examined the compatibility of the functional groups of the carboxylic acid part. In addition to the naphthalene ring, pyridine (1n-1s), quinoline (1t), benzothiophene (1u), ordinary benzene with different substituents (trifluoromethyl, sulfonamide, ester, methyl and fluorine atoms) Both the ring (1v-1aa) and the anthracene ring (1ab) can participate in the reaction, and the corresponding rearrangement products can be obtained with a moderate yield (27-74%).
It is worth mentioning that using this rearrangement reaction, cheap benzothiophene 2-carboxylate (1u, generated from the corresponding carboxylic acid ($20/g)) can be converted into a high value-added carboxylic acid derivative ( Produced by 2u hydrolysis, $13300/g); cheap 1-pyrene phenyl carboxylate (1ac) ($55/g) can be converted into 2-pyrene phenyl carboxylate (2ac, $454/g), which can be used for pyrene labeling Fluorescent biosensor; cheap 4-methyl-1-naphthoate (1ad, 1ae, generated from the corresponding carboxylic acid ($8/g)) can be converted to 1-methyl-3-naphthoate (2ad, 2ae), the hydrolyzate is a high value-added product ($ 2998/g). Good functional group compatibility and rapid conversion of cheap raw materials into high value-added products fully illustrate the practical application value of this reaction.
In the process of studying the range of substrates, the author found that when different positional isomers of carboxylic acid esters were used as reaction substrates, the same results were obtained when the reaction was performed under optimal conditions. For example, when 3-trifluoromethyl phenyl benzoate (2v) and 4-trifluoromethyl phenyl benzoate (1v) were reacted under optimal conditions, the ratio of 4- Phenyl trifluoromethyl benzoate (1v) and phenyl 3-trifluoromethyl benzoate (2v). This indicates that the reaction passes through the same intermediate, thus confirming that the reaction is reversible.
Finally, by combining the ester migration reaction with the decarbonylation reaction previously developed by their research group, the authors further studied the application of this reaction in synthesis. For example, under standard conditions, through ester migration reaction and carbon-hydrogen bond activation, 3-thiophenecarboxylic acid phenyl ester (1af) reacts with benzothiazole (4A) to obtain the 2-substituted thiophene-benzothiazole coupling product (3A) , Figure 5A), while the traditional decarbonylation coupling reaction yields a 3-position substituted product. As mentioned earlier, phenyl 4-picolinate (1n) will rearrange to phenyl nicotinate (2n) under optimal conditions. Interestingly, in the presence of large hindered diphenylamine (4B), this ester The migration reaction proceeded in the opposite way (ie 2n→1n), and then decarbonylation amination, yielding a 4-substituted amino coupling product with a yield of 62%, while the traditional decarbonylation coupling reaction yielded 3-position substitution The product. Since phenol itself is also a nucleophile, in the absence of an external nucleophile, phenyl quinolinecarboxylate and phenyl picolinate can be converted into corresponding migrating ether compounds by combining with the decarbonylation reaction. It is worth mentioning that when the reaction time of 1n was changed from 24 h to 48 h, the conversion of 1n→2n→3n (that is, two consecutive ester migration reactions) was successfully realized, and 2n was thermodynamically more than 1n. stable. However, decarbonylation etherification only proceeds at the C2 position of the pyridine carboxylate, so the reaction mainly produces 3D. In short, through clever use of this reaction, it can be foreseen that aryl esters can be converted into many compounds that are not easily obtained by traditional methods.
