Professor Huang Peiqiang's research group of Xiamen University: "one bottle" series reduction of secondary amides cyanation phosphorylation -- chemical selective synthesis of α - amino - α - cyanophosphonate

As phosphorus analogues of α - amino acids, α - aminophosphonic acid and its derivatives show various biological activities and are widely used in medicine, agriculture and other fields On the other hand, α - aminonitriles are important intermediates in organic synthesis and exist in many natural products and drug molecules as important structural units α - amino - α - cyanophosphonic acid and its derivatives are multifunctional compounds which combine the structural characteristics of the two compounds There are only a few reports about the synthesis methods, all of which are based on the starting materials with special structure, and the synthesis of these materials needs at least 3-4 steps Therefore, it is of great significance to develop a method for the synthesis of α - amino - α - cyanophosphonic acid from a simple substrate Recently, Professor Huang Peiqiang's research group of Xiamen University has constructed C-C bond and C-P bond on the carbonyl carbon of amides by using simple and easily available secondary amides as raw materials through series reduction cyanation and phosphorylation reaction, realizing the efficient synthesis of α - amino - α - cyanophosphonate The relevant results are published in org Lett (org Lett 2019, 21, 3808-3812) Brief introduction of Professor Huang Peiqiang's research group the research group is mainly engaged in organic synthesis research, including synthesis methodology, total synthesis of natural products, small molecule regulator chemistry and chemical biology (cooperation) Since 1991, more than 210 papers have been published in SCI source journals (including NAT Cummun., angew Chem Int ed., SCI Rep., chem Cummun., EUR J chem., etc.) Prof Huang Peiqiang, Professor, doctoral supervisor of Xiamen University, winner of National Science Foundation for Distinguished Young Scholars, member of Royal Society of chemistry At present, he is a member of Organic Chemistry Committee and chiral chemistry Committee of China Chemical Society Deputy editor in chief of Editorial Committee of organic chemistry, member of Editorial Committee of European Journal of organic chemistry international consultant, senior editorial committee of Chinese J Chem, Editorial Committee of Science China chemistry, Journal of chemistry, Chinese chemical letters and Journal of Xiamen University The honors and awards obtained mainly include organic synthesis contribution award of Organic Chemistry Discipline Committee of China Chemical Society (2007), honorary title of "advanced worker" of China Chemical Society (2010), excellent tutor award of Fujian Lucasian Education Foundation (2016), excellent editorial board of Chinese Science: Chemistry (2015, 2016) In 2017, he won the second prize of Natural Science Award for outstanding achievements in scientific research of institutions of higher learning of the Ministry of education Co editor or chief editor of monograph organic synthesis (Higher Education Press, 2004), organic name reaction, reagents and rules (Chemical Industry Press, 2008), efficiency in natural product total synthesis (editors: Pei ‐ qianghuang, Zhu ‐ Jun Yao, Richard P hsung; advanced by Professor Henry n C Wong, John Wiley & Sons, Inc, 2018 https://onlinelibrary.wiley.com/doi/book/10.1002/9781118940228 ）。 Cutting edge scientific research achievements: the "one bottle" series reduction cyanation phosphorylation reaction of secondary amides - chemical selective synthesis of α - amino - α - cyanophosphonate amides is a kind of simple and stable compounds, which are widely used as raw materials, intermediates and protection forms of amines in organic synthesis Secondary amides are also important guiding groups for functionalization of C-H bonds However, due to the fact that amides are the least carbonyl electrophilic compounds in carboxylic acid derivatives, the chemical selective direct conversion of amides is very challenging, which has attracted the research interest of many research groups at home and abroad in recent years Several research groups reported the synthesis of α - aminonitriles by reduction cyanation and alkylation cyanation of amides Zhao Yufen, academician of Xiamen University, used Schwartz reagent to develop the reductive phosphorylation of amides, which was directly converted into α - aminophosphonate (org Lett 2013, 15, 4214) Professor Huang Peiqiang's research group has been engaged in the study of direct conversion of amides for many years Based on the activation of amides by trifluoromethylsulfonic anhydride (TF 2O), the reductive diphosphorylation of secondary amides has been developed, and a convenient method for the preparation of α - aminodiphosphonate has been provided (org Lett 2015, 17, 732) On the basis of this work, Professor Huang Peiqiang's research group recently developed a series reduction cyanation phosphorylation reaction of SEC amides activated by trifluoromethylsulfonic anhydride (TF 2O) C-C bond and C-P bond were constructed on the carbonyl carbon of SEC amides at the same time to realize the efficient synthesis of α - amino - α - cyano phosphonate (org Lett 2019, 21, 3808-3812) Fig 1 Reduction cyanation phosphorylation of secondary amides (source: org Lett.) the author first optimized the reaction conditions with n-isopropylbenzamide as raw material, activated by trifluoromethylsulfonic anhydride (TF 2O), and reacted with tmscn and diethyl phosphite Under the optimized conditions, the target product α - amino - α - cyano phosphonate was obtained in 92% yield Subsequently, the authors examined a series of amide substrates (Fig 2) For benzamide substrate, the electronic effect of substituents on benzene ring has no obvious effect on the reaction, while the steric effect of ortho substituents has a certain effect on the reaction The reaction has good functional group compatibility and chemical selectivity The benzene ring can contain halogen, cyano, azo, ester and ketone carbonyl groups Benzamide N-substituents can be other alkyl groups, benzyl and allyl groups, but also compatible with ether, ester, halogen and other functional groups Aliphatic sec amides without α - h can also react smoothly At last, the author investigated the phosphite, which showed that the reaction was also suitable for dimethyl phosphite and diisopropyl phosphite Figure 2 Study on the application scope of substrate (source: org Lett.) in conclusion, the author developed a new method of "one bottle" synthesis of α - amino - α - cyanophosphonate from secondary amide This method has good universality, wide functional group compatibility and excellent chemical selectivity It is of great significance to study the biological activities and related applications of these compounds Under the guidance of Associate Professor Wang ai'e and Professor Huang Peiqiang, the above research work was completed by Chen Tingting, a graduate student The research work was supported by the national key R & D plan (2017yfa0207302), the National Natural Science Foundation (21672176, 21332007), the Yangtze River scholars and innovation team development plan of the Ministry of education and the Fujian Natural Science Foundation (2014j01062) 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.