Research group of Shen Qilong, Shanghai Institute of organic science, Chinese Academy of Sciences: Study on ipso trifluoromethyl sulfurization without transition metal participation

As a kind of highly active nucleophilic reagents, aryl boron lithium compounds have attracted a lot of chemists' interest in recent years At present, there are two main reaction modes of aryl boron lithium without transition metal participation: 1) when the intermodal position of aryl boron lithium has electron donor group, it can accept the activation of electrophilic reagent of another molecule, and then induce the stereospecificity of 1, 2-transfer, followed by elimination / aromatization to obtain stereospecific sp 2-SP 3 coupling products; 2) aryl boron lithium with electron donor or electron acceptor showed certain nucleophilic reaction activity, stereospecific reaction with a series of electrophilic reagents to sp 3-c However, the specific reaction mode of aryl lithium boron with electrophilic reagent to ipso SP 2 - C has not been reported Recently, the electrophilic trifluoromethylthio reagents with hyposulfonate structure developed by the research group of Shen Qilong of Shanghai organic Research Institute have been used for the first time to realize the transition metal free ipso SP 2-C trifluoromethylthio reaction (org Lett 2019, DOI: 10.1021 / ACS Orglett 9b02236) In recent years, many chemists have been interested in the study of the IPSO trifluoromethylthiolation of aryl boron lithium without transition metal as a highly active nucleophile At present, there are two main reaction modes of aryl boron lithium without transition metal participation: 1) when the intermolecular of aryl boron lithium has electron donor group, it can accept the activation of electrophilic reagent of another molecule, and then induce stereospecific 1,2-transfer, and then eliminate / aromatize to obtain stereospecific sp 2-SP 3 coupling product (Nat Chem 2014, 6, 584; J am Chem SOC 2016, 138, 9521; angelw Chem Int ed 2017, 56, 16318); 2) when the para position of aryl boron lithium has electron donor or electron acceptor group, it shows certain nucleophilic reaction activity and reacts with a series of electrophilic reagents to sp 3-C (j.am Chem SOC 2011, 133, 16794; J am Chem SOC 2015, 137, 10100 ) However, the specific reaction mode of aryl lithium boron with electrophilic reagent to ipso SP 2 - C has not been reported Fig 1 Aromatic boron lithium reaction mode (source: org Lett.) as a kind of important fluorine-containing functional group, fluoroalkylthiol has strong fat solubility and electron absorption The introduction of fluoroalkylthiol into the molecule can significantly change the fat solubility and metabolic stability of the molecule Shen Qilong group of Shanghai organic Research Institute has been committed to the creation of highly active electrophilic fluoroalkylthio reagents At present, the research group has developed several highly active electrophilic trifluoromethyl sulfur reagents (angelw Chem Int ed 2013, 52, 3457; angelw Chem Int ed 2013, 53, 9316; J org Chem 2013, 81, 7486); reported the first case of electrophilic, nucleophilic, self-contained difluoromethyl sulfur reagents (j.am Chem SOC 2015, 137, 15047; angelw Chem Int ed 2015, 56, 7648; angelw Chem Int ed 2016, 55, 15807); and the first electrophilic difluoromethylthiol reagent (angelw Chem Int ed 2017, 129, 11733) However, the reaction of electrophilic fluoroalkylthio reagents with aryl boron lithium has not been reported Therefore, it is worth studying and challenging to realize the direct ipso SP 2-C fluoroalkylthiolation without transition metal by the reaction of aryl boron lithium and electrophilic fluoroalkylthio reagents It was found that ipso SP 2-C trifluoromethyl sulfide can be obtained by the reaction of electrophilic trifluoromethyl reagent 1A with aryl borolithium reagent 2a in DMA / CH3CN (V / v = 1 / 1) at 60 ℃ for 24 hours, i.e with 75% yield of fluorine spectrum Under the optimal reaction conditions, the universality of the substrate was investigated A series of electron rich (3a-3e, 3i-3j, 3m-3u) and electron deficient substrates (3f-3h, 3k-3l) can obtain the corresponding trifluoromethane sulfonation products in medium to excellent yields The corresponding products of trifluoromethane sulfurization can be successfully obtained from aryl boron lithium containing ortho substituent (3R), meso substituent (3i-3o), para substituent (3a-3h, 3k-3o, 3q-3u) It is worth mentioning that for the aryl boron lithium substrates with electron donating substituents such as methoxy and dimethylamino groups, the coupling product of SP 2-SP 3 was not obtained, but the product of ipso SP 2-C trifluoromethylthiolation (3i-3j) was still obtained It is gratifying that the reaction can also be applied to heterocyclic aryl boron lithium substrates, including indole (3w), benzothiophene (3x), benzofuran (3Y), furan (3Z) and pyrazole (3V), and the heterocyclic trifluoromethylthiolation products can be obtained in medium yield At the same time, the reaction also has good functional group compatibility For common halogen, such as fluorine (3F, 3K), chlorine (3G, 3L), bromine (3H), phenolic hydroxyl (33), dimethylamino (3j), morpholine (3Q), acetal (3n), ketal (3T), olefin (3R), cyano (3S), trimethylsilyl (3U), etc protected by TBS are all well compatible (Fig 2) Figure 2 Substrate universality study (source: org Lett.) later, the author combined this reaction with iridium catalyzed C-H bond boration to realize high selective C-H bond trifluoromethane sulfonation modification Using this strategy, the author successfully achieved the C-H bond trifluoromethyl sulfurization of guaiazulene, a natural product At the same time, the author has also successfully realized the C-Cl bond trifluoromethylthiolation modification of Meclozine (Fig 3) Fig 3 Trifluoromethylthiolation of C-H and C-Cl bonds (source: org Lett.) in order to further demonstrate the practicability of the reaction, the author successfully realized a series of natural products, such as dihydrocholesterol derivatives (6), tocopherol (7) and trifluoromethylthiolation of red sandalwood (8) (Fig 4) Figure 4 Natural product trifluoromethylthiolation modification (source: org Lett.) in order to further verify the practicability of this method, the author took this reaction as a key step to realize the whole process of no transition metal participation in the synthesis of tiflorex (a drug already commercially available for the treatment of anorexia nervosa) (figure 5) Fig 5 Tiflorex synthesis (source: org Lett.) in order to explore the mechanism of this reaction, the author first carried out a free radical inhibition experiment When 1.0 equivalent free radical inhibitors, such as tempo, 1,4-dinitrobenzene and BHT, were added, the yield decreased under standard conditions, but the reaction was not completely inhibited At the same time, the formation of ring closing products was not observed in the free radical ring closing experiment, which indicated that there was no free radical process in the reaction In addition, the competitive experiments show that the reaction has excellent chemical selectivity 1A specifically attacks the electron rich thiophene ring to obtain the thiophene product of trifluoromethylthiolation, which further excludes the free radical mechanism (Fig 6) Figure 6 Mechanism exploration (source: org Lett.) in order to further explore the mechanism of the reaction, the author then carried out a kinetic monitoring of the reaction, and the data showed that the reaction was a first-order kinetics for the electrophilic trifluoromethylthio reagent 1a and aryl boron lithium with sulphonate structure, which indicated that both reagent 1a and aryl boron lithium were involved in the decisive step of the reaction Then, in order to explore the role of lithium ion in the reaction, the author carried out a control experiment, that is, under the standard reaction conditions, different equivalent 12-crown-4 was added to the reaction system The authors found that with the increase of 12-crown-4 equivalent, the yield decreased gradually, indicating that lithium ion played a crucial role in the reaction (Fig 7) Figure 7 Control experiment (source: org Lett.) in order to further understand the reaction process, the author worked with Mr Xue Xiaosong of Nankai University to carry out DFT theoretical calculation for the reaction The results show that there are Lewis acid and Lewis base interactions in lithium ion, electrophilic trifluoromethylthio reagent 1A with sulfite structure and oxygen atom of aryl boron lithium, which play an important role in reaction activity and chemical selectivity Under the activation of lithium ion, 1A undergoes a six membered ring transition state to carry out electrophilic trifluoromethyl sulfurization of aryl boron lithium; if undergoing the process of SP 3-C trifluoromethyl sulfurization, due to the space distance, lithium ion can not activate 1a, resulting in the activation energy higher than 8.2kcal/mol (Figure 8) Figure 8 DFT theoretical calculation (source: org Lett.) in summary, Shen Qilong group of Shanghai Institute of organic science, Chinese Academy of Sciences, used the electrophilic trifluoromethylthiolation reagent 1A with hyposulfonate structure developed by its group, and realized the first arylborolithium ipso trifluoromethylthiolation without transition metal participation The reaction conditions are mild, the substrate has wide applicability and the functional group has good compatibility By using this method, the author has successfully realized a series of natural products, C-H, C-Cl bond late trifluoromethylthiolation modification and the synthesis of drug molecule tiflorex Experimental results and DFT theoretical calculations show that lithium ion plays an important role in the reaction The reaction of boron lithium with other electrophilic fluoroalkylthio reagents is under further study The research results were recently published in the organizational letters (ASAP, DOI: 10.1021 / ACS Orglett 9b02236) Shen Feng, a doctoral candidate of Shanghai Institute of organic Sciences, was the first author of the paper The DFT theoretical calculation was completed by Mr Xue Xiaosong of Nankai University and Mr Zheng Hanliang The corresponding authors were Shen Qilong and LV long, researchers of Shanghai Institute of organic sciences Nowadays, people and scientific research have been paid more and more attention in the economic life China has ushered in the "node of science and technology explosion" Behind the progress of science and technology is the work of countless scientists In the field of chemistry, in the context of the pursuit of innovation driven, international cooperation has been strengthened, the influence of Returned Scholars in the field of R & D has become increasingly prominent, and many excellent research groups have emerged in China For this reason, CBG information adopts the 1 + X reporting mechanism CBG information website, chembeangoapp, chembeango official micro 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