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    Home > Trifluoromethylation of "jinshanshan"

    Trifluoromethylation of "jinshanshan"

    • Last Update: 2017-06-27
    • Source: Internet
    • Author: User
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    Drug chemists like to introduce trifluoromethyl (CF 3) into the molecular structure of drugs, because the existence of C-F bond strengthens the stability of drug metabolism in vivo, making the drug's efficacy more lasting There are many ways to introduce the CF 3 group into organic molecules The nucleophilic reagent (Rupert Prakash reagent), the electrophilic reagent (umemoto's or togni's reagents) and the metal complex (cucf 3) have corresponding applications Recently, Professor F Dean toste, an organic Daniel from the University of California, Berkeley, led the team to publish a science (Science 356, 1272 – 1276 (2017)), which reported the trifluoromethylation of Au (III) complexes to form C (SP 3) - CF 3 bond through the reduction process under the catalysis of "serendipitous discovery" F Professor Dean toste has been doing chemical research related to gold catalysis Although the latest published paper reported that the trifluoromethylation reaction was not catalyzed by gold, it also used the "glittering" gold complex The CF 3 group in the product undergoes the fracture and reconnection of C-F bond in the reaction process The author calls this reaction mechanism "fluoride rebound" mechanism A series of compounds containing trifluoromethyl and 18 f-labelled fatty fluorides were synthesized by using the interesting process of fluoride rebound Among them, radioactive fluorides can be used for the preparation of PET tracers In the design of PET tracers containing trifluoromethyl, it is noted that it is difficult to construct CF3 unit by nucleophilic substitution reaction The successful way to insert CF 3 into the tracer is to take CF 2 as the precursor, first form organic copper intermediate together with radioactive fluoride, and then obtain 18 f-labeled trifluoromethyl compound (Figure 1a) The problem that needs to be solved in this method is that difluoroalkyl metal compounds should have separation stability and be able to carry out the next step of radioactive fluorination reaction However, the Au (III) complex discovered by accident in the study just meets the requirements of experimental design (Figure 1b) Fig 1 Reverse synthesis analysis source of CF 3 radioactive synthesis: science first, the author obtained me-cf 3 and 3a by reaction of gold complex 1a and borane 2 (Fig 2a) During the reaction, 19 F NMR was used for monitoring, and it was found that the reaction was controlled by the first-order kinetics Then the author added 10 equivalent me3sibr into the same reaction, and obtained the gold complex 4 (Fig 2b); 4 reacted with AGF, and also obtained me-cf3 and 3a (Fig 2C) Therefore, the author proposed the reaction mechanism (Fig 2D): the metal complex 1 seized an F in CF 3 by borane 2 in the fluorine extraction process I, generated the Difluorocarbene intermediate, and then constructed the C-F bond through the alkyl migration insertion process II and reduction elimination process III, finally obtained me-cf 3 Density functional theory (DFT) calculation also confirmed that the migration and insertion process is easy to occur, and explained that Difluorocarbene intermediate is not easy to hydrolyze because of the low barrier Figure 2 Reaction research and reaction mechanism source: Science gold complex provides a new choice for the synthesis of trifluoromethyl compounds In this paper, we use simple gold complexes to prepare complexes with various functions through borohydride, cross decomposition, hydrogenation, aluminum lithium hydrogen reduction and so on, and finally eliminate them under the action of 2 to obtain trifluoromethyl products 8 and 11; aryl complexes can be used to synthesize leflunomide, allylic complexes can be used to synthesize Bayer lead compound Bay 59-3074 (cannabinoid receptor agonist) The experimental results show that au-c is still intact even under the harsh conditions of aromatics nitration, or through Simmons Smith cyclopropanation, osmium catalyzed dihydroxylation, periodate mediated glycolysis and palladium catalyzed cross coupling The gold complexes were stable when exposed to air or water and separated by silica gel column chromatography Only in the presence of CF 3So 3H and halogen, such as br 2, can au-c fracture be observed Figure 3 Various sources of trifluoromethylation products synthesized by gold complex: in the study of radiofluoride synthesis by science, the author found that acetate complex has both stability and reactivity Under the action of appropriate fluorine source and borane 2, nucleophilic reduction elimination reaction can be carried out (Figure 4a) However, the presence of KF and kryptofix [2.2.2] can successfully carry out 18 F labeling (Figure 4b) At last, 18 F labeled products were separated by prep HPLC and TLC, and their specific activity was tested Although the measured value is far lower than the alkyl fluoride synthesized by the classical nucleophilic substitution method, this method still has the potential for development in the future Figure 4 Research source of radioactive synthesis: Science
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