Professor Chen Tieqiao research group: nickel catalyzed SP3 c-cn bond breaking: phosphorylation of aliphatic nitrile derivatives

The activation of lead carbon carbon bond, especially the activation of non tension carbon carbon single bond, is one of the challenging topics, which not only has important academic value, but also has important industrial application value However, the reported methods usually use small ring tension or aromatization to drive carbon carbon bond activation, both of which lack universality In recent years, the activation of C - CN bond has attracted the attention of scientists In 2001, Miller first reported the cross coupling of nickel catalyzed benzonitrile with Grignard reagent (Figure 1a, path 1); using this strategy, chemists realized the cross coupling of arylnitriles (usually as solvents) with various heteroatom nucleophiles, and constructed the corresponding SP 2 C-Z bond (z = Si, B, P, etc.) (Figure 1a, Path 2); using transition metal catalysis, the direct hydrogenation and decyanation of nitriles has also been successfully realized (Fig 1a, path3); recently, the photocatalytic strategy has been applied to the field of c-cn bond activation, realizing the cross coupling of electron deficient heteroarylnitriles and active C-H compounds (Fig 1a, path 4) In addition, with the co catalysis of nickel and Lewis acid, the c-cn bond was successfully activated and transferred into C-C triple bond and double bond to generate corresponding alkenyl nitriles and alkylnitriles (Fig 1a, path 5) Recently, Morandi successfully avoided the use of highly toxic hydrocyanic acid as raw material to synthesize fatty nitriles by adding hydrocyanic acid generated from the decomposition of fatty nitriles and alkenes catalyzed by nickel Fig 1 C-cn bond activation to construct C-C bond or c-heterobond (source: org Lett.) although great progress has been made in c-cn bond activation, these reaction substrates are usually limited to SP 2 c-cn compounds or active benzyl nitriles Only a few examples of inactive SP 3 c-cn bond activation have been reported, and SP 3 c-cn, which is not active, is catalyzed by cheap metals The activation and transformation of bonds are still very challenging Recently, Professor Chen Tieqiao of Hunan University (now working in Hainan University) has made a new breakthrough in this field, using nickel as catalyst to realize the direct phosphorylation of SP 3 c-cn bond of alkylnitriles The relevant research results were published in org Lett (DOI: 10.1021 / ACS Orglett 8b02854) Prof Chen Tieqiao, born in Shaoyang, Hunan Province in January 1986, is currently a professor (Senior), doctoral supervisor and editorial board member of heteroatom chemistry, an International Sci journal In 2004, he was admitted to the school of chemistry and chemical engineering of Hunan University In 2005, he was transferred to the Chemistry Master's and master's combination class due to his excellent performance In 2009, he was transferred to the master's and master's combination class In April 2010, he went to Japan Institute of industry and Technology (AIST) to study and work for three years In 2013, he graduated from the doctor's degree In January 2014, he stayed as an assistant researcher and was promoted to associate professor in January 2017 In October 2017, he was transferred to Hainan University with Class C high-level talents and employed as a professor The master's supervisor is Professor Guo cancheng, and the doctoral supervisor is Professor Guo cancheng and Professor Han Libiao He has been engaged in and focused on the research of organophosphorus chemistry for a long time, covering many fields such as organic synthesis chemistry, organometallic chemistry, organophosphorus chemistry, pharmaceutical chemistry, etc Presided over 1 general program of NSFC, 1 youth program of NSFC (closed), 1 youth program of NSFC of Hunan Province (closed) In recent years, Professor Chen Tieqiao has published 47 SCI papers as the first author or corresponding author, including 4 papers of J am Chem SOC And 1 paper of angelw Chem Int ed., the top journal of chemistry, which has been cited for more than 900 times, with an H-index of 18 Leading research achievements: nickel catalyzed SP3 c-cn bond breaking: phosphorylation of fatty nitriles derivatives Dr Zhang Jishu of Hunan University accidentally found the direct phosphorylation of SP 3 c-cn bond in the cross coupling of arylnitriles and P (o) - H compounds to arylphosphines Using 2.5 mol% NiCl2 as catalyst, 1.5 equivalent t-BuOK as base, the reaction temperature is 120 ℃, 4-cyanophenylpropionitrile and diphenylphosphine (pH 2p (o) H) are heated in dioxane for 16 hours, and a new phosphorylation product is formed through sp 3c-cn bond breaking, the yield is 41% Inspired by this result, the author chose phenylpropionitrile (1a) and ph2ph (O2) as template substrates, and tried to realize the direct phosphorylation of this new SP 3 c-cn bond by further optimizing the reaction conditions (Fig 2) Fig 2 The optimization of reaction conditions (source: org Lett.) found that nickel catalyst was necessary for this reaction system When the reaction was conducted at 100 ℃ without nickel catalyst for 16 hours, the author only detected a small amount of coupling product 3A (entry 1) Under the similar reaction conditions, when 2.5 mol% Ni (COD) 2 was added as catalyst, the yield of 3A increased sharply to 43% (entry 2) Further increase the temperature to 120 ℃, and the yield of 3a is almost 100% (entry 3) Interestingly, stable and cheap nickel salts can also effectively catalyze the reaction (entry 4 and 5), which simplifies the operation of the reaction and greatly reduces the cost When t-buona, t-buoli and CS 2CO 3 were used as bases, the yield of 3A decreased under similar reaction conditions (entries 6-8) The reaction can also take place in other solvents (entries 9-12), among which dioxane is the best solvent Figure 3 Substrate development (source: org Lett.) under the optimal reaction conditions, the author next examined the applicability of the reaction substrate (Figure 3) In this reaction condition, benzyl nitriles and their derivatives can be easily coupled with ph2p (o) h to form corresponding ALKYLPHOSPHONATES It may be due to steric hindrance that the activity of o-methylbenzylnitrile is relatively low (3C) In addition to benzonitrile derivatives, the inert 3-phenylpropiononitrile derivatives are also prone to phosphorylation under nickel catalysis For example, 3-phenylpropiononitrile and its derivatives with electron donating groups on the benzene ring can react with ph2p (o) h to obtain the corresponding ALKYLPHOSPHONATES with high yield The polycyclic 3-arylpropiononitrile derivatives are also suitable for the catalytic reaction system Under the optimal reaction conditions, the reaction substrate containing indole, pyridine, carbazole and fluorine can also be coupled with ph2p (o) h to produce the corresponding organophosphorus compounds with high yield These results show that the reaction has potential application in the synthesis of related drugs and materials It is worth noting that 4-phenylbutyronitrile and 6-phenylhexonitrile can also undergo phosphorylation in this reaction system For P (o) - H compounds, aromatic and aliphatic secondary phosphorus oxygen are suitable for this catalytic system For example, bis (4-methylphenyl) phosphine and bis (2-naphthyl) phosphine are successfully cross coupled with phenylpropiononitrile to produce corresponding products 3Y and 3Z with high yield Under the reaction conditions, dibutylphosphorus and dicyclohexylphosphate are also effective coupling materials It is worth noting that the phosphorylation product 3j is a key intermediate in the synthesis of the anticancer drug combritastin A-4 (CA-4) (Fig 4, CA-4 is a cis stilbene compound extracted from Salix africana) In the total synthesis of CA-4, Pettit et al Synthesized intermediate 3j by two steps: first, benzyl chloride 5 was synthesized by the reaction of aldehyde 4 with water sensitive pH 2 PCL; then, compound 5 was reduced to intermediate 3j by NaBH 4 or bu 3 SNH In this reaction, the total yield of 3j is less than 50% In contrast, the synthesis of compound 3j in one pot with high yield is greatly simplified by the phosphorylation strategy developed by the authors and the coupling of commercially available benzyl nitriles with ph2p (o) H Figure 4 The synthesis of CommScope stop (source: org Lett.) further, the author carried out a gram scale reaction, and found that it can enlarge and the yield is not reduced, which means that the reaction has a better practical application prospect For example, at 120 ℃, 3-phenylpropiononitrile (10 mmol, 1.3 ml), ph2p (o) H (13.0 mmol, 2.66 g), NiCl2 (0.25 mmol, 32.5 mg) and t-BuOK (15.0 mmol, 1.67 g) reacted in dioxane for 16 hours At the end of the reaction, the volatile reagents were removed in vacuum The residue was separated by a short column to obtain the analytical product 3a, with a separation yield of 99% (Fig 5) Figure 5 Gram scale-up (source: org Lett.) based on the literature, the author proposed the possible mechanism of this reaction (Figure 6) The catalyst precursor NiCl2 was firstly reduced by P (o) - H compound to form active Ni (0) species, and then oxidized with SP 3c-cn bond to form intermediate a With the help of alkali, compound A and P (o) - H exchange ligand to form intermediate B, followed by reduction to eliminate the target product and regenerate the active Ni (0) species Fig 6 Possible reaction mechanism (source: org Lett.) in summary, the author has successfully developed a new type of direct phosphorylation of SP 3 c-cn bond catalyzed by nickel Under the standard reaction conditions, benzyl nitrile, 3-arylpropiononitrile, 4-phenylbutyronitrile and even 6-phenylhexonitrile can be successfully coupled with P (o) - H compound to produce the target product in medium to excellent yield This reaction can be successfully carried out at the gram scale (10 mmol) It can be used as a key step in the synthesis of the anticancer drug Commodore (CA-4) and simplify its synthesis route These results prove that this new reaction has potential application value in organic synthesis The corresponding authors of this paper are Professor Chen Tieqiao of Hunan University and Professor Han Libiao of Japan Institute of industrial technology 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.