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Rhodium-Catalyzed Synthesis of Isoquinolines

2021-09-01 来源: 51Due教员组 类别: Essay范文

各位留学生大家好!今天100due教员组给大家分享的是一篇化学essay代写范文,主要内容是讲:异喹啉及其衍生物具有广泛独特的生物活性和药理活性,已成为研究热点。近几十年来,人们报道了各种金属催化合成异喹啉的方法,其中铑催化剂以其良好的催化效率和官能团耐受性而著称,因此,铑催化合成因其能够快速组装复杂的异喹啉基序而被证明是一种有效的方法。本文按时间顺序综述了铑催化剂合成异喹啉的各种方法,并对其中的一些反应进行了详细的讨论。 


Abstract
With a wide range of unique biological activities and pharmacological activities, the synthesis of isoquinoline and its derivatives have become a research hotspot. Various metal-catalyzed synthetic methods of isoquinoline have been reported over the few decades, among the metal catalysts, Rh is notable for its good catalytic efficiency and functional group tolerance, thus, the rhodium-catalyzed synthesis has been proved as an effective method because it enables rapid assembly of complex isoquinoline motifs. In this paper, the methods of isoquinoline synthesis by rhodium catalyst have been reviewed in time order, and some of the reactions have been discussed in details.

Key Words:isoquinoline; Rhodium
Introduction
Isoquinoline and its derivatives are regarded as key motifs with diverse biological properties, they are not only the core structural unit of many natural products, but also the basic building blocks of many important drug molecules. Since discovery, isoquinolines have been widely used in the manufacture of dyes, antifungal drugs, insecticides intermediates, paints, etc. Because of the great importance of isoquinolines, the demand for versatile isoquinoline syntheses is continuous and strong, over the past few decades, various methods have been developed to synthesis corresponding aromatic heterocycle structure of isoquinoline.
The traditional method of synthesizing isoquinoline is Bischler-Napieralski method, Pictet-Spengler method, etc. However, these reactions are limited by many drawbacks, the conditions are harsh, the synthesis step is cumbersome, the starting material is not easy to obtain and the total yield is low. In comparison, the synthesis of isoquinoline by transition metal catalysis is an effective method, which has aroused great interest among the researchers. In recent years, transition metal-catalyzed C-H bond activation studies have made a rapid progress, based on these studies, the rhodium complex has provided a promising opportunity for high-efficient construction of isoquinoline structure, and the Rh-catalyzed direct C–H bond functionalization has been proved as a powerful tool to construct isoquinolines rapidly, also with diversity and functional group flexibility. 
The directing group plays an important role in the rhodium-catalyzed C–H bond functionalization. In the synthesis process, the guiding groups complexed with metal atoms to bring the metal catalyst close to the C-H bond to be activated. Also, the guiding groups can stabilize the reaction intermediates, thus promoting the reaction. In the rhodium-catalyzed system studies, many groups have developed a series of distinctive directing groups to help Rh-catalyzed C-H bond activation progress happen smoothly.
As the development of the research, it is researchers’ top priority to develop synthetic methods using minimally functionalized substrates and make the synthesis of isoquinolines become more flexible on the variety of functional groups and react under milder conditions. This review will focus on introducing the current available rhodium-catalyzed synthesis methods of isoquinolines. The methods will be introduced in chronological order and their progress will be summarized accordingly.
Methods of synthesis
In 2007, for the first time, the Japanese chemist Miura group published trivalent rhodium-catalyzed carboxyl-oriented C-H bond activation reaction. Then, in 2008, the Canadian chemist Fagnou group reported their acetamide-mediated C-H bond activation studies, also using trivalent rhodium-catalyst. Inspired by their groundbreaking research results, many groups have joined the research in this area.
In metal organic chemistry studies, the atoms on the imines are often used as coordination sites to complex with metal atoms to construct organometallic compounds. So, in the study of rhodium-catalyzed carbon-hydrogen bond functionalization, a series of imine-derived forms have been developed as a directing group to make C-H bond activation reaction happen.
There are mainly 2 types of rhodium-catalyze which can be used to synthesize isoquinolines. Rhodium(I)-catalyzed chelation-assisted C-H bond activation and Rh(III)-catalyzed cyclization.
Rhodium(I)-catalyzed method
In 2003, Jun group presented a Rh(I)-catalyzed C-H bond activation of common aromatic ketimines followed by direct ortho-alkenylation with 1-alkynes and internal alkynes.[1] In the reaction, the aromatic ketone, benzylamine and diphenyl alkyne are simply mixed by a one-pot process without the prior preparation of the corresponding ketimines, thus, the isoquinoline derivatives were synthesized convenient and highly efficient by the single step three-component reaction.

Graph 1 Jun’s method

In 2009, Cheng group described a Rh(I)-catalyzed synthesis method of substituted isoquinoline derivatives from various aromatic ketoximes and alkynes. [2] Like Jun’s work, this reaction is also a one-pot process without any further dehydrogenation or oxidation. In addition, the ketoxime substrates are readily prepared are quite stable, thus making the catalytic reaction of isoquinoline quite convenient and fast. This is synthesis process is also highly regioselective with unsymmetrical alkynes.
Rhodium(III)-catalyzed method
In 2009, Fagnou group reported oxidative isoquinoline synthesis using rhodium catalyst.[3] In the reaction, Fagnou used a variety of N-tert-butyl aryl aldimines as directing groups with an internal alkyne. The reaction used low-cost copper acetate as the oxidant, and can be carried out at 83 °C conditions successfully. In this report, cationic [Cp*Rh(MeCN)3][SbF6]2 catalyst was used for the first time. As a consequence, a rapid synthesis of multi-substituted isoquinoline was achieved under mild conditions, also the corresponding isoquinoline products are in good yield. It is proved that the aldimine coupling partner can be replaced by different substituents, including a variety of electron-donating and electron-withdrawing groups.

Graph 2 Fagnou’s method

Based on Fagnou’s previous research results, Miura group reported a reaction with phenylimine as the directing group. [4] In this report, although reactant alkyne is the same, due to the different substituents on the N atom, the reaction produced five-membered ring of indene instead of isoquinoline while the phenyl group on the N atom is also retained. Miura’s research demonstrated that in a condition of regioselective C–H bond cleavage, the rhodium-catalyzed oxidative coupling of aromatic imines with alkynes can proceed with high efficiency. However, the study also reveals that Cu(OAc)2 must be used in a stoichiometric amount as an external oxidant to form the final product. Both the work lead by Fagnou and Miura have proved that oxidative coupling between aldimines and alkynes can happen with the catalyze of Rh (III)Cp* complexes, while using a Cu(II) oxidant is indispensable in both two methods.[5]

This reaction has been further improved by Wang group in 2014, in which a manganese catalyst is used.[6] In rhodium-catalyzed isoquinoline syntheses from imines, generally an oxidant is needed to complete the catalytic cycle, However, in Wang’s research, it achieves dehydrogenative annulation of N–H imines and alkynes without an oxidant, this lead a new path to furnish isoquinolines. In this reaction, both diaryl and aryl alkyl ketimines can be expediently reacted, and the yield of isoquinoline derives can be as high as 92% This manganese-catalyzed method can be used to produce a wide array of isoquinolines with different functional groups and substitution patterns.

In 2010, Almost at the same time when the Fagnou group reported the methoxy-substituted formamide directing groups, Rovis Group of the United States reported a rhodium-catalyzed C-H bond activation reaction[7], in which methyl-substituted formamide work as a directing group. This report also obtained similar products as presented by Fagnou. But the reaction needs to be carried out in the conditions of 110 degrees Celsius, and the need to add copper acetate as oxidant, so it is not so satisfactory compared with Fagnou’s methoxy-substituted formamide method.

Graph 3 Rovis’s method

From previous reports, it shows that stoichiometric amounts of external oxidants are needed in many Rh-catalyzed approaches to sustain the catalytic turnover, this inevitably lead to a lower atom efficiency, since it will generate waste byproduct and have other unwanted side reactions. This problem of Rh-catalyzed synthesis is urgent to be solved. To avoid using external oxidants, a possible new strategy is try to use an internal multifunctional group that acts as both a directing group and an oxidant to regenerate Rh catalyst. It is notable that this kind of multifunctional group usually contains N-O bond (N-oxide and oxime, for example)
In 2010, The Chiba group of Nanyang Technological University, Singapore, reported a synthetic pathway of isoquinolines.[8] Chiba use aryl ketone O-acyl oxime derivatives and internal alkynes as reactant and [Cp*RhCl2]2-NaOAc as the potential catalyst system. In this report, he discovered a new directing group by introducing acetate into the oxygen atom of the ketoxime, hence the coupling reaction of acetophenone and acetylene was realized. In the process of reaction, acetate will depart from the atoms, so that it can achieve an intramolecular oxidation process, thus, the use of oxidants can be avoided and the atom economy of the reaction is greatly improved. In addition, the product has high regioselectivity when using asymmetric alkynes as substrates. However, the aryl groups and -OAc of the substrate oxime used in the process must be on the opposite side of the C = N double bond, this limits the variety of substrates for isoquinoline preparation. Hence, Chiba start using [Cp * RhCl2]2 as the catalyst, Cu (OAc) 2 as the external oxidant, the reaction of O-acetyl aryl ketone oxime with alkynes was catalyzed by both Cu and Rh to produce isoquinolines, both cis and trans oximes can be reacted, thereby broaden the range of isoquinolines synthesis.

Graph 4 Chiba’s method

Later in 2011, Li group reported a new method of rhodium (III)-catalyzed synthesis of isoquinolines.[9] In his reaction, Li use oxime as the directing group and CsOAc as the additive, the rapid formation of isoquinolines happened under mild conditions, also the reaction is not sensitive to moisture or air. As we can conclude from Chiba and Li’s report, the synthesis of isoquinolines from oxime derivatives does not require an external oxidant, because the N-O bond in oximes act as an internal oxidant in the reaction.

From above, we can see several reports which synthesize isoquinolines by C-H bond activation and use oxime as a directing group, although a lot of progress have been made, a mixture of regioisomeric products was observed in all reported reactions during the cyclization of ketoximes with unsymmetrical alkynes, this means the low regioselectivity is still a challenging task. 
In 2012, Jeganmohan group have reported Ru-catalyzed highly substituted isoquinolines derivatives synthesis excellent yields, with the presence of [RuCl2-(p-cymene)2] and NaOAc, the reaction achieves highly regioselective cyclization of heteroaromatic ketoximes with substituted alkynes. [10] At the same year, Ackermann group also reported on carboxylate free cationic ruthenium(II)-catalyzed redox-neutral annulations of alkynes with oximes as guide group.[11] Using ruthenium(II) complexes as catalyst provides anthor possible approach in isoquinoline synthesis.

In 2013, Cheng group in Taiwan presented a method for isoquinolines synthesis from arylhydrazones and alkynes via a [RhCp*Cl2]2 catalyst.[12] This reaction developed a new directing group-hydrazone by introducing a dimethylamino group at the imine atom. With the help of the directing group, rhodium catalyzes the ortho C-H bond activation and annulation, thereby obtaining a multi-substituted isoquinoline product.After completion of the reaction, the dimethylamino group is removed from the nitrogen atom, so that it is not necessary to introduce an additional oxidizing agent. Hydrazone is a very rare directing group for C-H bond activation reaction.

Graph 5 Cheng’s method
In 2014, Li group has found that with the use of aziridinylimines as practical substrates, benzylidenehydrazones will occur an oxidative tandem reaction with alkynes in the presence of [(RhCp*Cl2)2]/AgNO3/Cu(OAc)2 catalytic system. This is a quite novel reaction for the synthesis of isoquinolines.[13]

Although multifunctional group method has made a huge progress compared with previous method, like Chiba and his co-workers presented, it still suffered from low atom economy since these oxidizing parts contained in the reactants are not combined with the desired products.
To solve this, in 2014, Huang demonstrated a rhodium-catalyzed synthesis of isoquinolines from ketazines and internal alkynes. [14]Sequential C−H and N−N bond activation happens at room temperature, wherein the N−N bond cleaved and acted as an internal oxidant, while both nitrogen atoms on ketazine substrates could be efficiently incorporated to isoquinoline products. This synthesis pathway is clear and simple, which able to realize in any open container at room temperature without adding any external oxidants. This is among the mildest reaction conditions for isoquinolines synthesis.

Graph 6 Huang’s method

In 2015, Sun reported a high efficiency method to produce isoquinolines from aryl hydrazines and internal alkynes while hydrazine as the directing group. [15]This reaction can happen under mild conditions(80℃, air ), and for the first time it realized diazo molecules the C–H bond activation and N–N bond cleavage. It also has some notable advantages, the directing group is simple, the substrates can be prepared easily, external oxidants are not necessarily needed and adding benzoic acid provide an effective way to facilitate the catalytic cycle. In the experiment, hydrazine and alkyne were employed in [Cp*RhCl2]2 - benzoic acid system, change other kind of Rh catalysts or change solvent will cause the reaction became sluggish or even inert. However, using un-symmetric diaryl alkyne will generate two Regio-isomers in nearly 1: 1 ratio.
On the bases of this reaction, Sun and his co-worker presented a possible mechanism. In the presence of [Cp*RhCl2]2, the ortho-C–H activation of reactant occurs with the help of N atom in hydrazine. This activation will produce the first intermediate. Then it will insert to alkyne to form another intermediate, a molecule which contained a seven-membered ring. Then with the existence of air and benzoic acid reductive elimination of this iminium cation would lead to the formation of isoquinoline and regeneration of the [Rh III] species under a redox process.

Graph 7 Sun’s method

Conclusion
In summary, these rhodium-catalyzed reactions provide straightforward routes to produce isoquinoline and derivatives, which are useful intermediates for various fine chemicals including medicines and organic materials. Although many effective methods have been proposed for the synthesis of isoquinoline, none of the methods can be applied to all substrates, therefore, the development of higher regioselectivity, higher catalytic activity of transition metal complex catalysts and the research to explore more suitable reaction conditions to isoquinoline synthesis is still the focus of future research.

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