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    Home > Research group of Professor Bi Xihe of Northeast Normal University: using trifluoroacetaldehyde n-o-trifluoromethylphenylsulfonylhydrazone as a new precursor of trifluoromethyldiazomethane and its application

    Research group of Professor Bi Xihe of Northeast Normal University: using trifluoroacetaldehyde n-o-trifluoromethylphenylsulfonylhydrazone as a new precursor of trifluoromethyldiazomethane and its application

    • Last Update: 2019-01-31
    • Source: Internet
    • Author: User
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    The introduction of trifluoromethyldiazomethane (cf3chn2), as a kind of high activity trifluoromethylation reagent, is often used in cycloaddition, X-H insertion, coupling and homologation reactions The existing method can only obtain the gas or solution of CF 3chn 2 by oxidizing trifluoroethylamine hydrochloride in acid condition CF 3 CHN 2 is explosive and toxic by itself, so it is usually accompanied by potential danger in use Although researchers have developed some advanced operation methods in recent years, the use of special reaction devices is still a limitation Therefore, it is still an important challenge to develop new reagents that are easy to handle and can slowly produce CF 3 CHN 2 in situ under mild conditions Recently, Professor Bi Xihe's research group of Northeast Normal University has made a breakthrough in the new generation strategy of CF 3chn 2 The group designed and synthesized a new precursor of CF 3chn 2, tfhz TFs, which can release CF 3chn 2 slowly under alkaline condition, and realized the X-H hydrofluoronization reaction, Doyle kirmse reaction and cyclopropane reaction participated by tfhz TFs Relevant results were published online in naturecommunications (NAT Commun 2019, 10, 284) Figure 1 Synthesis and transformation of CF 3 CHN 2 (source: Nat Commun.) brief introduction of Professor Bi Xihe, Professor of School of chemistry, Northeast Normal University In 2008, he began his independent research work in the field of organic synthesis chemistry, focusing on the study of silver catalyzed organic chemistry More than 70 papers have been published in Chem SOC Rev., NAT Commun., J am Chem SOC., angew Chem Int ed., org Lett., chem Commun., etc., and a book "silver catalyst in organic synthesis" (2018) Co edited by Professor Li Chaojun and Wiley VCH Professor Bi Xihe has successively won the "excellent young science foundation" of NSFC (2015), the "Yangtze River scholars Award Program" of Ministry of Education (2016) and the Royal Society of Chemistry (FRSC) (2018), and won the first prize of natural science of Jilin science and Technology Award (ranking first) in 2018 Frontier research achievements: using tfhz TFs as a new precursor of trifluoromethyldiazomethane and its application research CF 3chn 2 is a kind of high activity trifluoromethylation reagent, which has important application in various synthesis and transformation However, the single synthesis method of CF 3chn 2 has been a huge obstacle in its development CF 3chn 2 can only be prepared by oxidation of trifluoroethylamine hydrochloride in acid condition, and the production conditions are extremely limited At the same time, the manual operation of highly toxic and explosive CF 3chn 2 gas or solution also leads to a great potential safety hazard in the use process Tfhz TFs was used as a new precursor of CF 3chn 2 It can release CF 3chn 2 slowly under alkaline condition Tfhz TFs has been applied to the synthesis of x-h-difluoroalkenes, which provides a new strategy for the synthesis of heteroatom substituted difluoroalkenes that are difficult to be synthesized by other methods In addition, the efficient Doyle kirmse reaction and cyclopropane reaction also proved the synthesis efficiency of the new reagent First of all, the conditions of the reaction were screened by using p-Methylthiophenol 1 as the model substrate (Fig 2) The optimum conditions are as follows: Fe [P2] (1 mol%) as catalyst, Koh aqueous solution (20 wt%) as base, DCM (1 ml) as solvent, SDBS (30 mol%) as additive, under 40 ℃, 1 and tfhz TFs reaction for 18 hours, 80% of the separation yield can be obtained Figure 2 Optimization of reaction conditions (source: Nat Commun.) next, the author studied the substrate range of Thiophenol (Figure 3, method a) Among them, the yield of thiophene (2-19) is very good when it has electron donor and electron acceptor substituents The ortho -, meso -, or para substituents on the aromatic ring do not affect the yield of the reaction, and the ortho disubstituted substrate with high steric hindrance also yields the product (20 - 21) Thiophene, furan and 2-naphthalene mercaptan can also react smoothly (22-24) In addition, the product (25) was also obtained in good yield The product 9 was oxidized to sulfone 9 ', and its structure was confirmed by single crystal X-ray diffraction Furthermore, the author investigated other heteroatom nucleophiles, first of all, the amido difluorenolation (Fig 3, method B) The optimum reaction conditions were Cu (OTF) 2 (20 mol%), lithium TERT butanol (4.0 equivalent) as base, DCE: toluene (3:1) as solvent and argon at 40 ℃ The reaction range includes all kinds of aniline derivatives, among which the substituents such as halogen, cyano, ketone, ester and anthraquinone are all obtained in medium to good yields (26 - 35) In addition, diphenyl ketone imine is also a feasible substrate The product (36) was obtained in 51% yield However, the reaction efficiency of secondary amines was very low (37) Next, the author studied the reaction of schildofluorenylation of alcohols (Fig 3, method c) Benzyl, alkyl and heteroaryl substituted alcohols can be obtained in good yields The position of substituents on aromatic hydrocarbons of benzyl alcohols had no effect on the reaction results (38 - 47) The second and third grade benzyl alcohols were also suitable (48 and 49) Alkylalcohols (such as phenylethyl and phenylpropyl substituted alcohols) and other functionalized alcohols (such as cinnamyl, propargylic and 2-adamantyl substituted alcohols) can be obtained in medium to good yields (50-56) In contrast to aliphatic alcohols, 4-biphenylphenol has poor reactivity, and only 20% yield of 4-biphenylphenol is obtained (57) In addition, the author has studied the amido difluoroenylation of various natural products, drugs and pharmaceutical intermediates, all of which can produce products (58 - 65) in medium to good yields Fig 3 The application of tfhz TFs in the reaction of amido difluorenesylation (source: Nat Commun.) further, the author tried to synthesize in gram scale (Fig 4) Using the commercial fettppcl as catalyst and reducing the amount of catalyst, the author also achieved the same yield (47%) as Fe [P2] In the application of the product, the author found that 66 (67%) cis - vinylidene fluoride sulfide can be obtained by 9 under the catalysis of copper, and there is no other effective method to synthesize the compound at present In addition, in the presence of Nah, 9 and excessive p-methoxyphenol can undergo double defluorination Figure 4 Gram level experiment and product application experiment (source: Nat Commun.) in order to study the reaction mechanism of this reaction, the author designed a control experiment (Figure 5) The DCM solution of CF 3chn 2 was prepared by using the previously reported method, and KOH aqueous solution was replaced by pure water under standard conditions It was found that the product of hydrofluoroethylation could not be obtained, and the reaction could only obtain the product of trifluoroethylation in 61% yield When KOH aqueous solution is used, the product can be obtained in 48% yield It is shown that the base plays a key role in the alkylation of difluoroalkenes It can promote the reaction of heteroatom nucleophiles and the elimination of β - F In addition, 2 'and 68 can't be converted into the product of amidofluorenylation under the standard conditions, which proves that 2' and 68 are not the reaction intermediates Figure 5 Control experiment (source: Nat Commun.) later, the author proposed the reasonable mechanism of the reaction (Figure 6) First, in-situ production of CF 3 CHN 2 by tfhz TFs in alkaline condition, which reacts with metal catalyst to form carbene intermediate a; a is captured by the substrate to obtain ylide B, B is deprotonated in alkaline condition to obtain intermediate C, which is eliminated by β - F to obtain the product of amido difluoroenylation Figure 6 Possible reaction mechanism (source: Nat Commun.) next, the author studied the applicability of tfhz TFs in Doyle kirmse reaction with allyl / allynyl sulfide (Figure 7) In the study of the application scope of the substrate, the author found that the aryl thioether containing electron donor and electron acceptor can get the product in a very good yield (69 - 83) Disubstituted aryl, naphthyl and heteroarylallyl thioethers are also suitable for this reaction (84 - 86) Benzyl, methyl and diallyl substituted alkylallyl thioethers also showed good tolerance (87 - 89) When the R 1, R 2 and R 3 of allylthioether are substituted by different substituents, the conversion and enantioselectivity of allylthioether are high (90 - 99) In addition, a variety of aryl, heteroaryl, alkyl and endoalkyne functionalized propargyl thioethers can obtain the target product (100 - 106) in good yield Figure 7 Application of tfhz TFs in Doyle kirmse reaction (source: Nat Commin.) finally, the applicability of tfhz TFs in cyclopropane reaction with olefins was studied (Figure 8) Various functionalized styrene derivatives of aryl, condensed aryl and heteroaryl have very high conversion and enantioselectivity (107 - 115) Conjugated diene and conjugated alkyne also have very good reaction efficiency (116 - 118) Finally, 1,1-disubstituted olefins also showed good tolerance (119 and 120) Fig 8 Application of tfhz TFs in cyclopropane reaction (source: Nat Commin.) conclusion: a new precursor of CF 3 CHN 2, tfhz TFs, has been developed by Professor Bi Xihe of Northeast Normal University It can produce CF 3 CHN 2 in a controlled way under alkaline conditions, avoiding excessive accumulation of diazo compounds At the same time, tfhz TFs showed excellent performance in the first realization of X-H bond (x = s, N, O, Se), Doyle kirmse reaction and cyclopropane reaction, and provided a variety of efficient synthesis methods of novel compounds 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, chembeangoapp, chembeango official microblog, CBG wechat subscription number and other platforms jointly launch the column of "people and scientific research", approach the domestic representative research group, pay attention to their research, listen to their stories, record their demeanor, and explore their scientific research spirit.
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