Research group of Professor Zhao Xiaoming, Tongji University: iridium catalyzed chemical selectivity, regioselectivity and enantioselective allylation of hydroxylamine

Lead hydroxylamine (NH2OH) has two reaction sites: nitrogen and oxygen Oxygen and nitrogen are directly linked and interact with each other Iridium catalyzed allylation will generate complex mixed products It is very difficult for NH2OH to undergo chemical and stereoselective allylation In order to improve the chemical selectivity and avoid the polyallylation of amines, benzyl (BN) or benzoyl (BZ) are generally used to protect hydroxylamines, and iridium catalyzed allylation is carried out as nucleophilic nitrogen reagent or nucleophilic oxygen reagent, respectively Recently, Zhao Xiaoming, Professor of Tongji University, used unprotected hydroxylamines to synthesize chiral N-allyl hydroxylamines through the regulation of reaction conditions The related results were published on organic letters (DOI: 10.1021/acs.orglett.9b01357) Professor Zhao Xiaoming's research group is devoted to design and discover new reactions, and develop them into useful synthesis methods for the synthesis of target molecules such as bioactive molecules, functional materials and natural products Emphasis: new methods of fluorination and fluoroalkylation Research on nonlinear materials, fluorescent and phosphorescent materials Prof Zhao Xiaoming introduced himself to Tongji University in April 2008 He was appointed professor and doctoral supervisor Graduated from Dalian University of technology He studied in the United States for eight years in 1998-2004 and 2006-2008 He is a postdoctoral and senior associate researcher at the University of Florida and the University of Southern California In 1995-1998 and 2004-2006, he was engaged in postdoctoral study and work in Shanghai Institute of organic chemistry, Chinese Academy of Sciences, and served as an associate researcher (visiting professor in the group of S.I Murahashi, Japan for a short time) In 2010, he was selected as "Pujiang talent" in Shanghai In 2012, he won the Thieme Chemistry Journal Award 2012 Leading scientific achievements: iridium catalyzed chemical selectivity, regioselectivity and enantioselective allylation of hydroxylamine; nitrogen chemistry has attracted the attention of organic chemists due to its important applications in life, medicine and chemical industry Common nitrogen-containing reagents such as ammonia, hydroxylamine and hydrazine are prepared by Haber Bosch reaction of nitrogen, hydrogen and oxygen (Science 2018, 360, 6611) Hydroxylamine is used as reducing agent in organic synthesis, and also condenses with carbonyl compounds to form oxime So far, nitrogen or oxygen protected hydroxylamines have been reported to be used in transition metal catalyzed asymmetric allylic substitution reactions, and chiral C-N or C-O centers have been constructed respectively (chem - EUR J 2013, 19, 16746; org Lett 2011, 13, 2810; org Lett 2004, 6, 4631) These methods have the following shortcomings: (1) the product needs to be deprotected in further derivatization; (2) due to the introduction of protective groups such as BN, R and BZ, the stereoselectivity and regioselectivity of the reaction will decrease (EQ-1 and eq-2 Figure 1) The above problems can be avoided by using unprotected hydroxylamine as nucleophilic reagent (eq-3 Figure 1), but the stereoselectivity of the reaction needs to be solved The chemical selectivity of nitrogen and oxygen on hydroxylamine and the inhibition of further allylamine reaction of the product should be considered Fig 1 The application of NH 2 Oh derivatives in iridium catalyzed allylation (source: orrg Lett.) the author systematically screened and optimized the reaction conditions with methyl cinnamate as the substrate and hydroxylamine hydrochloride as the nucleophile Under the optimal conditions, N-allyl hydroxylamine with optical activity was obtained, and the ratio of branched chain products to linear products (regioselectivity) was more than 20:1 On the other hand, the formation of diallyl amination products was observed When the amount of allyl carbonate is excessive, diallyl amination products are mainly produced; when the amount of hydroxylamine is excessive, diallyl amination is inhibited, and the enantioselectivity of diallyl amination products is 96% with 70% yield Subsequently, the universality of the substrate and the compatibility of the functional groups were examined (Fig 2) The results show that the substrates with electron donating groups and multi substituents with high steric resistance have high yield and stereoselectivity If the substrate has electron absorbing groups, such as halogen, nitro group and trifluoromethyl group, the yield is slightly reduced, but the stereoselectivity is still high For heterocyclic substrates, the corresponding product 3S was obtained in 69% yield, and its enantioselectivity was as high as 97% It is worth noting that the yield of 3T is 87% and the enantioselectivity is 92% Figure 2 Study on the application scope of substrate (source: org Lett.) the method can be enlarged to gram scale, realizing the synthesis of n-allylamine product 3O, laying the foundation for the application of n-allylamine product (Figure 3) The hydroxylamine on the product can be used as the amino equivalent For example, in the presence of zinc powder, acetic acid and water, the hydroxylamine is reduced to the corresponding allylamine 5 In the presence of ozone, the double bonds on the amines can be oxidized to carboxylic acids, thus 5 can be converted to chiral α - amino acids This is also a new way to synthesize α - amino acids The absolute configuration of the product was determined to be r by comparing the literature of known compound (R) - 5 At the same time, N-allyl hydroxylamine has higher nucleophilic property, which can further produce allyl amination reaction, and allyl product 6 can be produced with 90% yield and excellent stereoselectivity (DR > 20:1) Fig 3 Research on product application (source: orrg Lett.) in conclusion, N-allyl hydroxylamination was realized by iridium catalyzed asymmetric allylation with hydroxylamine as nucleophile This method has single chemical selectivity, high enantioselectivity and regioselectivity, which solves the problem of polyallylamine, and provides a new way for the synthesis of chiral allylamine This achievement was recently published on organizational letters (DOI: 10.1021/acs.orglett.9b01357) The author of this paper is: jitengchen, Qingchun Liang, xiaomingzhao * The above research work was supported by NSFC 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.