Recently, the research group led by Tang Wenjun at the Hangzhou Institute for Advanced Study, UCAS (hereinafter referred to as HIAS) and the Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences has developed an efficient palladium-catalyzed intermolecular Heck reaction between N-heteroaryl halides and heterocyclicolefins through the innovation of phosphine ligands and the catalytic model. Leveraging this reaction, the group has efficiently formed a series of chiral α-heteroaryl-substituted heterocycles. The method features a broad substrate scope, excellent functional group compatibility and mild reaction conditions. Using the method, the research group completed the efficient synthesis of anabasine and (S)-nicotine and their analogues.
01
Background Introduction
Chiral α-heteroaryl-substituted heterocycles are widely found in many natural products and drug molecular structures with significant biological activity. For example, (S)-nicotine is a major component in tobacco that affects central nervous system diseases, and the alkaloid Harmicine has antispasmodic, antipyretic, and anticancer properties. Valbenazine has been approved for the treatment of tardive dyskinesia (TD) (Figure 1).
Figure 1 Natural Products and Biomolecules Containing Chiral α-heteroaryl-substituted Heterocyclic Fragments
Chiral α-heteroaryl-substituted heterocyclic synthesis has been challenging for the projects focusing on asymmetric synthesis and drug research.Structurally, the intermolecular Heck reaction between N-heteroaryl halides and heterocyclic olefins is one of the most direct and practical methods for the synthesis of these chiral fragments. In recent years, the development of chiral catalysts and catalytic systems has effectively promoted asymmetric Heck reactions. Many research groups at home and abroad, like those of Hayashi, Tietze, Pfaltz, Hou Xuelong and Zhou Jianrong, have made outstanding contributions to the formation of chiral α-heteroaryl-substituted heterocycles using asymmetric Heck reactions. However, the asymmetric Heck reaction between N-heteroaryl halides and heterocyclic olefins has been a pending problem, the key to which is catalyst deactivation caused by the strong coordination between N-heteroaryl compounds, especially pyridyl structures, and transition metals. Thus, reports on successful examples have been rare (Figure 2).
Figure 2 Asymmetric Heck Reaction Between N-heteroaryl Halides andHeterocyclic Olefins
02
Highlights
1) The research group designed and developed a P, P=O-based ligand with large steric hindrance, through which the compatibility problem of the palladium-catalyzed Heck reaction with N-heteroaryl halides was effectively solved, and the reaction activity and substrate scope were significantly improved. 2) Using electron-rich DTBM-SEGPHOS with large steric hindrance as a chiral ligand and adopting the cationic palladium catalysis model, the research group enabled the highly enantioselective Heck reaction of pyridine substrates. The efficient synthesis of (S)-nicotine and its analogues was achieved by using asymmetric Heck reactions. 3) This method, featuring a broad substrate scope, excellent functional group compatibility, and mild reaction conditions, provides an efficient and simple synthesis strategy for chiral α-heteroaryl-substituted heterocyclic compounds.
03
Graph and Text Analysis
The research group began the research by taking 3-bromopyridine (1a) and tert-butyl 3,4-dihydropyridine-1(2H)-carboxylate (2a) as template substrates.Since the products of Heck reactions are usually olefin migration mixtures, the crude products of Heck reactions were directly hydrogenated to form a single reduction product3a for product characterization and yield calculation.The research group initially screened representative monophosphorus ligands for commercial purposes (e.g. SPhos, QPhos and BI-DIME (L1)), bisphosphorus ligands (including Me-DuPhos, Ph-BPE and BINAP), and ligands based on five-membered benzooxaphosphane (L5-L8). None of these reactions resulted in the target product, indicating that the Heck reaction containing pyridyl functional groups was indeed challenging.Encouragingly, when the P, P=O-based ligandL4 was used, the product3a was yielded from the reaction in a 31% yield, indicating that the P, P=O ligand can significantly promote the tolerance of pyridyl-containing functional groups.After further optimizing the structure and reaction conditions of the P, P=O ligand, the research group found that L9 was the optimal ligand, and MeOH and Pd(OAc)2were the optimal solvent and catalyst precursor (Figure 3).
Figure 3 Condition Optimization
Under optimal conditions, the research group firstexamined the substrate scope of the Heck reaction (Figure 4). The reaction of 3-bromopyridine and 3-bromopyridine containing electron-rich substituents with tert-butyl 3,4-dihydropyridine-1(2H)-carboxylate can produce the corresponding products3a-c in good yields (75-80%).The reaction yield for meta-substituted pyridine substrates was reduced slightly (72%).In addition, the corresponding products 3e-g can be produced in moderate yields by using ortho, meta-disubstituted 3-bromopyridines as substrates.Notably, this method is suitable for substrates containinglarge steric hindrance substituents and variedly substituted substrates. For example, when 2,3-dihydropyran was used as an olefin substrate, its reaction with 3-bromopyridine (3k) and other N-heteroaryl bromides, including ortho-substituted (3l-n), meta-substituted (3o) or ortho-, meta-disubstituted (3p-3r) substrates and those containing multiple heteroatoms (3s), could produce the corresponding products in a yield of 65-87%.Similarly, the Heck reaction between tert-butyl 2,3-dihydro-1H-pyrrole-1-carboxylate and pyridyl,quinolyl, and pyrimidinyl bromides could yield the corresponding products 3u-3ad in moderate to good yields (65-88%).Moreover, the research group evaluated the Heck reaction between 2,3-dihydrofurans and N-heteroaryl bromides (3ae–3ap). They found that the reaction could happen between pyridine substrates containing substituents such as Me, F, CF3, and CF2H and brominated heteroaryl substrates based on quinoline, pyrimidine, isothiazole, and indazole skeletons. Thus, the universality and practicability of the methodology were demonstrated.
Figure 4 Heck Reaction Between Brominated N-heteroaryl Ring and Heterocyclic Olefin
To clarify the acting mechanism of the P, P=O ligand L9 in promoting Heck reactions of N-heteroaryl halides, the research group prepared the complex compound [Pd(L9)Cl2] and conducted the steric hindrance analysis of [Pd(L9)Cl2] and the previously reported [Pd(L11)Cl2], using the SambVca 2.1 Web program (Figure 5b).The results showed that the complex compound [Pd(L9)Cl2] (% Vbur = 57.6) with an anthryl group possessed a morecongested catalytic pocket than [Pd(L11)Cl2] complex (% Vbur=51.1) bearing a dimethylamino group, resulting in effectively inhibiting its coordination with N-heteroaromatic rings and improving the stability of palladium catalysts. Meanwhile, due to the weak P=O coordination, the coordination site occupied by P=O of the Pd (II) complex was easy to release after the oxidative addition, allowing better coordination between olefin substrates and the palladium center to ensure the subsequent migratory insertion process.
Figure 5 Ligand Structure-Reactivity Analysis
The research group further studied the asymmetric Heck reactions.When chiral P, P=O ligands were used, the enantioselectivity of the products was poor. The possible reason could be that the release of the P=O coordination from the Pd center during olefin coordination resulted in the loss of effective enantioselectivity control during the migratory insertion step. The research group subsequently proposed that the enantioselectivity of the reaction might be improved through the use of chiral bisphosphorus ligands and the clever use of cationic palladium catalysis pathways (Figure 7a). After systematic examination of several representative chiral phosphine ligands, the research group found that the enantioselectivity of the product4a was as high as 96% ee when (S)-DTBM-SEGPHOS was used as the ligand (Figure 6).Under optimal conditions, the research group studied the substrate scope of asymmetric Heck reactions betweenN-heteroaryl halides and 2,3-dihydrofurans. Electron-rich 3-bromopyridines with substituents at the ortho position provided the products4b-ein good yields (61–80%) and high ee (96–97%). Similarly, the products4f-k containing electron-withdrawing substituents (2-F, 2-CHF2, 2-CF3, 2-COOEt, 2-COMe, and 2-pyridyl) were also successfully synthesized in moderate yields (52-65%), with excellent enantioselectivity (91-98%).In addition, the method had good tolerance to bromides containing substituents at the ortho position, and the target products 4zand4ac were synthesized with excellent enantioselectivity.The research group also explored the substrate scope of 4-bromopyridine containing various functional groups, and the substrates under study could be converted into products, including4ad, 4ae and4af, in good yields (63-70%) and high ee (95-98%).Notably, the method had good compatibility with heteroaryl structures containing multiple heteroatoms, such as pyrazine (4ah), pyrimidine (4aj), isothiazole (4ak) and pyrazole (4ai, 4al), and the obtained products featured good enantioselectivity (86-97%).In addition to N-heteroaryl bromides, 2-bromothiophenes and 3-bromo-1-benzothiophenes could also be used as electrophilic reagents for the reaction, and the corresponding products4am and4an could be synthesized in moderate yields and with good enantioselectivity.Besides, the research group also explored the asymmetric Heck reaction where theN-Boc-2,3-dihydropyrrole was used as a heterocyclic olefin. Through its reactions with bromopyridines and bromoisoquinolines, highly optically active products 4aoand4ap were obtained.
Figure 6 Asymmetric Heck Reaction Where Brominated N-heteroaryl Ring Is Involved
The research group proposed a stereoscopic model for asymmetric Heck reactions where (S)-DTBM-SEGPHOS was used as a chiral ligand. Under the action of CF3COOAg, the bromine atom in the oxidative addition complex was dissociated from the palladium to form a cationic Pd species with a vacant coordination site for the subsequent olefin coordination. Due to the space environment of the Pd catalyst in coordination with (S)-DTBM-SEGPHOS, the research group believed that the coordination at the Re surface of cyclic olefins (like dihydrofurans) and the Pd center was more favorable. In addition, the olefins were located in the lower right area of the quadrantal diagram, essentially avoiding spatial repulsion with the aryl component of the ligand in the upper right area. The tertiary stereogenic center adjacent to oxygen atoms was then generated through migratory insertion. Furthermore, the research group pointed out that the efficiency of the asymmetric catalytic reaction of dihydropyran or tetrahydropyridine substrates needed to be improved at present. The research group speculated that the steric hindrance effects and half-chair conformation of the six-membered ring substrate structure were not conducive to the occurrence of Heck reactions (Figure 7b).
Figure 7 Asymmetric Heck Reaction and Stereochemical Model
To verify the practical value of this method, the research group used Pd/L9 as the catalyst and enabled the intermolecular Heck reaction between 3-bromopyridine (1a) and tert-butyl 3,4-dihydropyridine-1(2H)-carboxylate (2a) at the gram scale. After hydrogenation, the product 3awas obtained in a 70% yield. Anabasine was then successfully synthesized by removing the N-Boc protecting group from3avia CF3COOH (Figure 8a).In addition, the research group completed the asymmetric Heck reaction between 3-bromopyridine (1a) and 2,3-dihydrofuran (2d) at the gram scale. The product4a was produced in a 74% yield and with 96% ee.The subsequent palladium-carbonhydrogenation of4aprovided the compound (S)-3u in a 99 % yield and with 96% ee (Figure 8b).(S)-Nicotine is a potent dopamine receptor agonist. Using Pd(OAc)2 and (S)-DTBM-SEGPHOS catalysts, the research group achieved the asymmetric Heck reaction between 3-bromopyridine (1a) and2c, through which the chiral product6 was synthesized in a 64% yield and with 94% ee.After the subsequentcatalytic hydrogenation and reduction of LiAlH4, the highly optically active nicotine7 was obtained (Figure 8c).
Figure 8 Synthetic Application
04
Summary and Expectations
The research group of Wenjun Tang at the School of Chemistry and Materials Science, HIAS and the Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, through the development of a P, P=O ligand with large steric hindrance and a new catalytic model, has completed Heck reactions ofN-heteroaryl halides to effectively synthesize a series of chiral α-heteroaryl-substituted heterocycles. Using electron-rich DTBM-SEGPHOS with large steric hindrance as a chiral ligand and adopting the cationic palladium catalysis pathway, the research group has enabled the highly enantioselective Heck reaction of pyridine substrates for the first time. The method, featuring a broad substrate scope, excellent functional group compatibility, and mild reaction conditions, provides an efficient and simple synthesis strategy for bioactive molecules containing α-heteroaryl-substituted heterocyclic skeletons. It is expected to be applied in new drug R&D and chemical process development.
This project was funded by the National Key R&D Program, the National Natural Science Foundation of China, the Chinese Academy of Sciences, the Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, and theKey-Area Research and Development Program of Guangdong Province.
05
Introduction to the Research Group
1. Information on Research Fellow Tang Wenjun
Tang Wenjun, a doctor and research fellow, graduated from East China University of Science and Technology with a bachelor's degree in Fine Chemical Engineering in 1995, from the Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences with a master's degree in 1998 (supervisor: Academician Ma Dawei), and from Pennsylvania State University in the USA with a doctoral degree in 2003 (supervisor: Prof. Zhang Xumu). From 2003 to 2005, he was a postdoctoral fellow at Scripps Research Institute, the USA (supervisor: Prof. K. C. Nicolaou). He worked as a senior scientist at the Pharmaceutical Technology Department, Boehringer Ingelheim, the USA from 2005 to 2009 and the principal scientist from 2009 to 2011. Since July 2011, he has been a research fellow and project leader at the Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences; meanwhile, he is a professor and doctoral supervisor at the School of Physical Science and Technology, ShanghaiTech University, a chief professor of HIAS, and a doctoral supervisor at the School of Pharmacy, East China University of Science and Technology. In 2015, he won the China Youth Award for Homogeneous Catalysis. In 2017, he was selected as the recipient of the National Science Fund for Distinguished Young Scholars. In 2018, he was selected as the Young and Middle-Aged Leading Talent in Science and Technology Innovation awarded by the Ministry of Science and Technology of the People's Republic of China. In 2019, he won the Scholar Award of Wuxi AppTec Life Science and Chemistry Awards.
2. Research Objective: large-scale synthesis of bioactive moleculesResearch Objective: large-scale synthesis of bioactive molecules
Research Field I — Efficient, practical and green catalysis methodologies. Transition metal catalysis is one of the most active areas in modern organic synthetic chemistry.Transition metal catalysts are the key to the whole processes of catalytic reactions involving transition metals, and the characteristics of ligands, including electronic effects, steric effects, and spatial effects, directly affect the activity and selectivity of these catalysts. The development of chiral phosphine ligands has greatly promoted the whole field of asymmetric catalysis. In the past few years, our research group has designed and developed a series of P-chiral phosphine ligands that have remarkable structural characteristics and show excellent efficiency in large steric hindrance coupling, asymmetric coupling, asymmetric cyclization, and asymmetric hydrogenation. This offers a practical and green catalysis methodology for efficient synthesis of complex natural products and drugs.
Research Field II — Total synthesis of complex natural products. Utilizing the synthesis methodologies developed by our research group, we carry out high-efficiency total synthesis and large-scale preparation of some natural products with significant physiological activity, and engage in relevant pharmacochemical studies.
Research Field III — Green Synthesis of Drugs. New reaction or synthesis strategies that can be industrialized, efficient and economical will be developed, and efficient synthesis processes for drugs or pesticide molecules studied.
The Studio is looking forward to postdoctoral fellows with ideals and ambitions. If you are interested, please contact research fellow Tang Wenjun.
Link for the Studio's Website: http://wenjuntang.sioc.ac.cn/
Source | School of Chemistry and Materials Science
Typesetter | Wang Zhe
Executive Editor | Wang Xia
