The deuterium reaction of aldehydes catalyzed by light and small organic molecules

Lead deuterium as a marker plays an important role in the study of reaction mechanism, absorption, distribution, metabolism and excretion (ADME), nuclear magnetic resonance spectroscopy and mass spectrometry In recent years, the introduction of deuterium atoms into drug molecules, while maintaining the basic pharmacological activity of drugs, has been developing rapidly in order to enhance the metabolism and pharmacokinetics of drugs In 2017, the FDA approved the first deuterium drug, austedo, to enter the market Compared with the parent product of butylbenzazine, deuterium butylbenzazine has a longer half-life, and its pharmacokinetic characteristics have been significantly improved As a result, the demand of deuterium drugs in the pharmaceutical industry is increasing, which greatly promotes the research of deuterium reaction methodology Recently, Professor Wang Qingmin's research group of Nankai University has made a great breakthrough in this field They combine hydrogen atom transfer photocatalyst with organic small molecule mercaptan catalyst, and use deuterium instead of water as deuterium source to realize highly selective deuterium reaction of aldehydes This method can be used for deuterium modification of medicine, pesticide and natural products in the later stage, which provides an efficient and practical method for the research and development of deuterium drugs Relevant research results were published in Chem SCI (DOI: 10.1039/c9sc05132e) Wang Qingmin research group of Nankai University is affiliated to the State Key Laboratory of elemental organic chemistry and the school of chemistry of Nankai University and Tianjin collaborative innovation center of chemical industry At present, the research group has more than 20 teachers and graduate students The current research work of the research group includes: separation, identification, total synthesis and structural transformation of natural pesticides; molecular design, synthesis, biological activity and structure-activity relationship of new and efficient green chemical pesticides; total synthesis of natural products and efficient construction of heterocyclic molecular framework; free radical reaction under photocatalysis to build heterocyclic molecules He has published more than 200 papers in J agric Food chem., pest manag SCI., SCI Adv., angel Chem Int ed., chem SCI., org Lett., etc Prof Wang Qingmin, Ph.D., Professor, doctoral supervisor Born in March 1970, graduated from the Department of modern physics, Lanzhou University with a bachelor's degree in radiochemistry in 1994, and obtained master's degree in organic chemistry and doctor's degree in agricultural pharmacy from Nankai University in 1997 and 2000 respectively In June 2000, he received a doctorate degree and stayed in school He was promoted to associate professor in December 2000, professor in December 2004 and doctoral supervisor in 2005 In 2004, it was selected into the "new century excellent talents support plan" of the Ministry of education, and in 2017, it was selected into the leading talents of Shandong Taishan industry (high-efficiency ecological agriculture innovation) Mainly engaged in the research and development of natural pesticide, green chemical pesticide and drug Since the work was carried out independently, I have worked in the international authoritative journal J agric Food chem., pest manag SCI., SCI Adv., angel Chem Int ed., chem SCI., Arts & Rheumatism, j.med Chem., org Lett., chem Commun., adv synth Catalyst, Chem.eur J et al Published more than 200 papers included in SCI; applied for more than 90 invention patents in China, the United States and Europe with the first inventor, authorized more than 50 invention patents in China, the United States and Europe; published 3 works (chapters) A new clean production method of biomimetic pesticide pyrethroid series products, major pesticide varieties and high-end fine chemicals has been invented, which has been successfully applied to industrial production and has produced huge economic benefits A number of super efficient fungicides for plant virus disease control, green insecticides and acaricides as well as national class I new drugs have been created, which are in different stages of industrial development It has undertaken more than 30 scientific research projects, such as the national special fund for outstanding doctoral dissertation authors, the National Natural Science Foundation, the national science and technology support plan, 973 project, the national key R & D plan, the key project of the Ministry of education, the key project of Tianjin applied basic and cutting-edge technology research plan, and the special scientific research fund for the doctoral discipline point of colleges and universities He won the National Excellent Doctoral Dissertation in 2002, the 2003 Youth Chemistry Award of China Chemical Society, the 2005 invention patent award of Tianjin, the 2007 Life Chemistry Research Award of Wuxi apptec, the 2010 10th Tianjin Youth Science and technology award, the 2010 13th China Association for science and technology, the 2015 outstanding youth achievement transformation award In 1997, the 9th Dabei agricultural science and technology award, the 5th Nankai University "dedicated" award, the first prize of teaching gold, and four times won the title of "excellent doctoral dissertation instructor of Nankai University" 21 doctoral students and 41 master's students have been trained and graduated, and they have won the National Excellent Doctoral Dissertation nomination award, Tianjin excellent doctoral dissertation, Nankai University Excellent Doctoral Dissertation, Nankai University excellent master's dissertation and national scholarship Frontier scientific research achievements: light and organic small molecules cooperate to catalyze the deuterium reaction of aldehydes Aldehydes are ubiquitous in medicine and organic synthesis, and aldehydes can be converted to a variety of other structural units through specific chemical transformation Deuterated aldehydes can be used as ideal deuterated synthetic blocks to construct more complex molecular structures Therefore, it is of great significance to develop efficient synthesis methods to obtain deuteroaldehyde At present, the synthesis methods of deuterated aldehydes include reduction of corresponding esters by liald 4 and reoxidation, reduction of corresponding amides by Schwartz reagent (prepared by liald 4), reduction and carbonylation by Pd / Rh co catalysis, and deoxidation and deuterization of carboxylic acids by photocatalysis and organic small molecule co Catalysis (Fig 1a) Considering the atom and step economy in organic synthesis, the most ideal method to prepare deuterium aldehyde is hydrogen deuterium exchange reaction (HIE) In this field of jurisprudence, several cases of HIE reactions catalyzed by IR and Ru have been reported, but the deuterization rate of these reactions is not high and the regioselectivity is not good, and the by-products of deuterization of C-H bond of aromatic ring are often obtained (Fig 1b) In addition, the introduction of deuterium into aldehydes with complex structures is also a challenge in organic synthesis Considering the importance of deuterium substituted aldehydes, the author hopes to develop a new reaction mode, using deuterium substituted water as deuterium source, to realize the high efficiency, atom and step economy of acyl selective hie reaction In addition, the author hopes that this new hie reaction can be applied to the late deuterium generation of aldehydes with complex structures Visible light catalysis has developed rapidly in organic synthesis in recent years Recently, Macmillan group reported the HIE reaction of the n-o-h bond of tertiary amines under photocatalysis The key to the success of the reaction is to transfer deuterium atom by using organic small molecule mercaptan as deuterium atom transfer catalyst The author hopes that the selective deuterization of aldehydes can be realized by the strategy of hydrogen atom transfer to produce acyl radicals from aldehydes, and then by the strategy of thiol catalyzed deuterium atom transfer Tungsten metal (bu4n) 4 [w10o32] salt (tbadt) is a common metal catalyst for hydrogen atom transfer (HAT), which is prepared by one-step reaction of sodium tungstate It can grab Hydrogen atom of inert hydrocarbon bond to produce alkyl radical The bond energy of hydrocarbon bond on benzaldehyde aromatic ring (113 kcal / mol) is much higher than that of aldehyde hydrocarbon bond (94 kcal / mol), which will ensure that (bu4n) 4 [w10o32] photocatalyst can selectively seize the hydrocarbon bond of aldehyde to produce acyl radical However, the bond energy (80-88 kcal / mol) of sulfur hydrogen bond of common mercaptan catalysts is lower than that of aldehyde hydrogen bond, so the acyl radical produced can quickly grab the deuterium atom of sulfur and deuterium to get deuteroaldehyde, and this process also conforms to the polarity matching principle in the process of free radical hydrogen capture (Fig 1c) Therefore, the combination of (bu4n) 4 [w10o32] photocatalyst and organic small molecule mercaptan catalyst provides a strategy of free radical hie for the synthesis of deuterium aldehydes So far, the cooperative catalytic mode of (bu4n) 4 [w10o32] photocatalyst and mercaptan catalyst has not been reported In this paper, we report a selective deuterization of hydroformyl using deuterium water as deuterium source under the catalysis of photocatalysis and organic small molecules (Fig 1D) The mild reaction conditions, high deuterium rate, wide range of substrate application and good functional group compatibility make the reaction particularly suitable for deuterium modification of drug molecules Fig 1 deuteroaldehyde and synthesis method (source: chem SCI.) the author selected the reaction conditions by using 2-naphthaldehyde (1a) as reaction substrate, tbadt as photocatalyst, dichloromethane and deuterium water as reaction solvent (Table 1) First of all, the author screened the mercaptan catalyst When 2,4,6-tris-isopropylthiophenol (7a) was used, the target product 10A (entry 1) could be obtained with 94% deuterium substitution rate in 4 days When other mercaptan catalysts were used, the deuterization rate decreased (entry 2 – 4) When N-methylpyrrolidone, acetonitrile and chloroform were used as mixed solvents, the deuterium rate of the reaction would be reduced (entry 5-7) Reducing the amount of tbadt photocatalyst to 2 mol%, the deuterium yield of the reaction to 77% (entry 8); reducing the equivalent of mercaptan catalyst 7a to 20 mol%, the deuterium yield of the reaction to 80% (entry 9) In the end, the author did further control experiments, and the reaction could not occur without photocatalyst, mercaptan catalyst or light (entry 10-12) So far, the author has obtained the best reaction conditions: 4 mol% tbadt as hat photocatalyst, 40 mol% 2,4,6-diisopropylphenylmercaptan (7a) as mercaptan catalyst, dichloromethane and deuterium water as mixed solvent for 4 days Table 1 screening of reaction conditions a (source: chem SCI.) under the optimal reaction conditions, the author investigated the application scope of the reaction substrate (Table 2) The yield of separation is 92% in 10 years, which shows that the deuterium products will not decompose in column chromatography The target product (10b) can be obtained from 6-methoxy-2-naphthaldehyde with a deuterium substitution rate of 92% However, 1-Naphthaldehyde can get the product (10c) with 90% deuterium substitution rate, and the relatively low deuterium substitution rate may be due to the larger steric resistance of the substrate, while the process of capturing aldehyde hydrogen atom by tbadt photocatalyst is affected by steric resistance effect In order to further investigate the functional compatibility of the reaction, the benzaldehyde substrates with various substituents on the benzene ring were investigated (10d – 10bb) Specifically, the substrate with neutral groups such as isopropyl, tert butyl and phenyl substituents on the benzene ring can obtain the target product (10d-10f) with good deuterium substitution rate Moreover, the deuterium products (10g-10k) can be obtained from the substrates with halogen substituents such as fluorine, chlorine, bromine and iodine Trifluoromethyl and Trifluoromethoxy groups play an important role in improving the properties of drugs The author found that trifluoromethyl and Trifluoromethoxy groups can also be compatible in the reaction system (10L – 10o) The deuterium products (10p-10v) can also be obtained from benzaldehyde with higher deuterization rate by electron absorbing groups such as ester group, cyano group and electron donating groups such as methoxy group, ether and amine More importantly, some sensitive functional groups such as boric acid and alkyne