JACS: Yu Jinquan research group of Scripps Institute realizes β - C (SP3) - H olefinization of free carboxylic acid

In the past ten years, the directed C (SP 3) - H activation of fatty acids with various guiding groups has provided a new fracture mode for organic synthesis, while the carboxyl directed C (SP 3) - H activation reaction has rarely been reported, and this kind of reaction can only be carried out under the condition of using exogenous additives In 2010, Yu Jinquan group reported for the first time that PD (II) catalyzed β - C (SP 3) - H olefinization of n-arylamide and acrylate (scheme 1, EQ 1) The electron absorbing n-arylamide perfluoride promoter is very important for C (SP 3) - H activation In 2014, the new tricycloquinoline ligands were used to improve the efficiency of β - C (SP 3) - H alkylation of amides, which made the alanine derived amides successfully alkylated (scheme 1, EQ 2); then, under the combined action of quinoline ligands and weak coordination amide guiding groups, scheme 1 of amides was realized for the first time, EQ 3) and this kind of reaction will be followed by the side reaction of cyclization with nitrogen-containing auxiliaries Recently, Maiti group realized γ - C (SP 3) - H olefinization by using bidentate guiding group, but only limited to the substrate containing quaternary carbon center (scheme 1, EQ 4) Scheme 1 C (SP 3) - H olefinization of carboxylic acid derivatives (photo source: j.am Chem SOC.) recently, the residual gold right research group of Scripps Institute in the United States has realized β - C (SP 3) - H olefinization of free carboxylic acids (scheme 2) for the first time by using acetyl protected amino ethyl phenylthioether ligands Relevant papers were published in j.am Chem SOC (DOI: 10.1021 / JACS 8b06527) 。 The γ - lactones produced by this method are widely found in many bioactive compounds (Figure 1), and useful β - olefin fatty acids or 1,4-dihydroxy compounds (scheme2) can be obtained by hydrolysis and ring opening of lactones Scheme 2 β - C (SP 3) - H olefinization of carboxylic acids and their lactones (picture source: J am Chem SOC.) Figure 1 γ - lactones and their derived bioactive compounds (picture source: J am Chem SOC.) the author first used 2,2-dimethylbutyrate 1b as model substrate and benzyl acrylate 2A as olefin coupling mate A preliminary study on the carboxyl - oriented olefinization of β - C (SP 3) - h was carried out Under the conditions of Na 2HPO 4 · 7h 2O as base, Ag 2CO 3 as oxidant and Pd (OAC) 2 as catalyst, the olefinization product 3B (Table 1) was obtained in 16% yield Next, the author tested the self-developed pyridine or quinoline ligands, and the yield was increased to 57% by using simple single tooth 2,6-dimethylpyridine ligands After extensive screening of different bases and external oxidants, the author found that the product 3B could be obtained with 70% separation yield in the presence of 2,6-dimethylpyridine using K2HPO4 as base and agoac as oxidant However, the use of this ligand is limited to carboxylic acids containing α - quaternary carbon centers In order to overcome this limitation, the authors turned their attention to bidentate ligands to accelerate the activation of C (SP 3) - H The first to be tested was a single - N - protected amino acid (MPAA) ligand Experiments show that the substrate can only get low yield under the action of this kind of ligands Other bidentate ligands can promote the activation of enantioselective intermolecular C (SP 3) - H, resulting in a medium yield of substrate 1b, but have no reactivity to carboxylic acids containing α - H Because the nHAC group plays an important role in the bidentate ligands, the authors try to use sulfur instead of quinoline and oxazoline as σ - donors, and prepare the acetyl protected amino ethyl phenylthioether ligand L14 With the increase of reaction temperature and the use of PD (TFA) 2, the separation yield was further increased to 96% It is worth mentioning that L14 is stable in the reaction and easy to recover after the reaction In addition, the formation of γ - lactone by intramolecular conjugation can avoid other C-H functionalization in the presence of multiple β - C-H bonds In order to study the effect of ligand structure on the reaction efficiency, the ligand L14 was studied systematically The results showed that the protective group of amino group had a significant effect on the reaction: the yield decreased significantly when AC was replaced with TFA, BZ, BOC or CBZ, indicating that nHAC may participate in the C (SP 3) - H cracking process Substituting σ - donor oxygen or nitrogen for sulfur atoms will result in the loss of ligand activity, and the thioligands protected by alkyl or AC will not be active, which reveals the importance of PHS The authors suggest that the thioether ligands have two functions in the olefinization: (1) accelerating the initial reaction speed by 20 times; (2) making Pd catalyst more stable in the reaction time and providing higher conversion Table 1 Development of ligands (photo source: J am Chem SOC.) after obtaining the best ligands and reaction conditions, the author screened the application scope of aliphatic acid substrates (Table 2) A variety of α - dialkyl substituted propionic acids can be allylated to obtain the required γ - lactone; the phenyl in the carboxyl β - or γ - position has good tolerance, even if there is a reactive ortho C (SP 2) - H bond, the substrate is still resistant When there are heteroatoms such as oxygen or nitrogen in the substrate, β - C (SP 3) - H is also tolerated The newly developed ligand L14 broadens the application scope of carboxylic acid substrate containing reactive α - h under standard conditions Considering the importance of α - aminolactone, the allylation of n-phthaloyl-alanine substrate is very attractive The scheme can also be extended to the allylation of C-H bond of cyclopropyl and cyclobutyl to obtain condensed bicyclonolactone The presence of hydroxyl and halogen in the lactone provides a reaction site for its further derivatization Table 2 Application scope of carboxylic acid substrate (photo source: J am Chem SOC.) next, the author used neopentyl acid 1A as carboxylic acid substrate to screen the application scope of olefin coupling components (Table 3) The results show that all kinds of acrylate derivatives can be olefinized, and the electron absorbing groups, such as amides, ketones, nitriles, sulfones and phosphonates, which are linked to alkenes, are resistant to the olefinization conditions, and the target γ - lactones can be obtained in high yield Under the optimized conditions, the author also found that N-aryl or alkyl maleimide is a suitable coupling component, and a variety of spiropyrrolidine can be obtained in high yield Table 3 Application scope of olefin substrate (photo source: J am Chem SOC.) in order to prove the practicability of C (SP 3) - H olefinization product, the author uses neopentanoic acid 1a and benzyl acrylate 2a to olefinize to get γ - lactone 3A (yield 93%, gram scale) Then 3A was successfully converted into three kinds of synthetic blocks with different structures: (1) γ - lactone 5A was obtained by selective hydrolysis of ester in acid condition, which can be converted into other compounds by carboxyl reaction; (2) adipic acid derivative 5B was produced by hydrolysis in sodium hydroxide condition; (3) 1,4,6-triol 5C (scheme 3) was obtained by reduction of lactone and ester Scheme 3 C (SP 3) - H alkylation gram scale experiment and synthesis application (picture source: J am Chem SOC.) conclusion: the research group of residual gold rights has developed an acetyl protected amino ethyl phenylthioether bidentate ligand to promote the activation of C (SP 3) - H, and realized the C (SP 3) - H alkylation of downstream dicarboxylic acid catalyzed by Pd (II) for the first time without the aid Then, the author lactonized the product by 1,4-adding pair of olefins The reaction has a single selectivity in the presence of multiple β - C-H bonds High value of β - olefin or γ - hydroxy fatty acids can be obtained by ring opening of the prepared γ - lactone products In addition, considering the challenges of using alkyl halides for Heck coupling, the reaction provides a useful alternative.