Chiral iridium complex and preparation method and application thereof

Abstract

This application discloses a chiral iridium complex, its preparation method, and its applications. The chiral iridium complex of this application has the structure shown in Formula 1, where X is a halogen or sulfonate group, and R, R1, R2, R3, R4, R5, and R6 are independently selected from methyl, ethyl, methoxy, ethoxy, N,N-dimethyl, n-propyl, isopropyl, tert-butyl, trifluoromethyl, phenyl, substituted phenyl, and halogen. The chiral iridium complex of this application can be used as a catalyst for asymmetric reductive amination and asymmetric hydrogen transfer reductive amination reactions, catalyzing the one-step synthesis of chiral primary amines from ketone substrates. It has advantages such as a wide substrate applicability and high catalytic activity. The chiral iridium complex of this application exhibits good stability in air and can be stored directly in air. This chiral iridium complex provides a new scheme and route for the synthesis of chiral primary amines via asymmetric reductive amination reactions, laying the foundation for the industrial synthesis of asymmetric reductive amination reactions and chiral primary amines.

Description

Technical Field

[0001] This application relates to the field of chiral primary amine catalyst technology, and in particular to a chiral iridium complex, its preparation method, and its application. Background Technology

[0002] Chiral primary amines are widely found in natural products, pharmaceuticals, and pesticide molecules, serving as crucial chiral building blocks. In new drugs developed over the past 20 years, the proportion of chiral primary amine structural units has been increasing. For example, in 2020, approximately 35% of the top 200 best-selling small molecule drugs globally contained at least one chiral amine fragment. Chiral primary amines play a vital role in drug molecule design; some drug molecules themselves contain chiral primary amine fragments. Derivatization of primary amine groups can rapidly enrich the compound library, thereby accelerating the development of amine drugs. On the other hand, chiral primary amines can be used as chiral ligands, small molecule organic catalysts, and chiral resolving agents, finding wide and important applications in organic synthesis. For instance, optically pure 1,2-diphenylethylenediamine is a key component of Noyori-type bisphosphine diamine catalysts. The introduction of this chiral fragment can significantly accelerate the rate of ketone hydrogenation to alcohol and plays a crucial role in controlling the enantioselectivity of the reaction. Chiral primary amines derived from natural products, such as quinine, can be used as small-molecule organic catalysts, exhibiting excellent catalytic performance in a variety of organic reactions. Furthermore, (R)-α-phenylethylamine is a commonly used chiral resolving agent, used for the chemical resolution of the antibiotic fosfomycin, which has a good therapeutic effect on Gram-related infections. Due to the importance of chiral primary amines, developing efficient, low-cost, and atom-economical methods for their synthesis is of great significance for the advancement of asymmetric catalysis and medicinal chemistry.

[0003] The synthesis of chiral primary amines mainly relies on the resolution of racemic mixtures. While simple and effective, this method only yields a theoretical maximum of 50%. With the rapid development of enzyme catalysis technology and processes, biocatalysis has emerged as a mild, green, and efficient tool for the synthesis of chiral primary amines in recent years. Its practicality has been demonstrated in the synthesis of some drugs, such as the diabetes drug sitagliptin. In contrast, methods for synthesizing chiral primary amines using chemical catalysis are still very limited and mainly rely on multi-step synthetic strategies. For example, current main strategies for preparing chiral amines include the reduction or addition of imines, the conversion of enamines, the hydroamination of alkenes, the allyl amination, and the direct amination of CH bonds. Most of these methods require the pre-preparation of substrates with nitrogen-protected groups, the generation of secondary or tertiary amines through chemical transformation, and then deprotection to obtain the more synthetically valuable chiral primary amine. This limits atom and step economy and generates a large amount of waste. Furthermore, some substrates, especially imines and enamines, are unstable, making synthesis difficult and limiting the available substrates.

[0004] Metal-catalyzed asymmetric reductive amination is one of the most direct methods for obtaining chiral amines. Using readily available ketones and amine sources as raw materials, and in the presence of a reducing agent such as hydrogen and a chiral metal catalyst, chiral amines can be constructed in one step, with water as the theoretical only byproduct. Compared to the widely used imine reduction, direct ketone reductive amination avoids the pre-preparation of unstable imines. When ammonia or its equivalents (such as ammonium salts) are used as the amine source, prochiral ketones can be directly converted into chiral primary amines via reductive amination. This method offers high atom and step economy and effectively reduces waste emissions. Compared to traditional chemical synthesis methods, it is simpler and greener, making it an ideal strategy for preparing chiral primary amines. Ammonium salt-involved reductive amination reactions face many challenges, including: (1) the ketone carbonyl itself can be reduced, and the in-situ condensation to form an imine is reversible, leading to chemoselectivity issues; (2) the in-situ generated ammonia or the primary amine product can coordinate with a metal, resulting in poisoning and low reaction efficiency; (3) the coordination of amines may also lead to ligand exchange with the metal, increasing the difficulty of chiral control of the reaction; (4) primary amines may undergo secondary reductive amination with the carbonyl group, making the reaction products extremely complex. These challenges have hindered the development of this field. Given the importance of chiral primary amines, scientists have conducted long-term research on imine-catalyzed asymmetric hydrogenation and direct reductive amination of ketones involving ammonium salts.

[0005] Metal-catalyzed asymmetric hydrogenation of imines is one of the most common and direct methods for preparing chiral amines. The direct asymmetric reductive amination of ammonium salts with ketones is a multi-step process, in which the reduction of the unprotected NH imine intermediate (or its corresponding imine cation) is the key step and the enantioselectivity-determining step. Studying the asymmetric catalytic hydrogenation of unprotected NH imines is crucial for ultimately achieving direct asymmetric reductive amination involving ammonium salts. Unprotected NH imines are typically difficult to prepare and isolate, and exhibit poor stability, making the study of asymmetric catalytic hydrogenation of NH imines extremely challenging. To address this issue, in 2009, Zhang Xumu's team collaborated with scientists at Merck to develop a practical method for preparing NH imine hydrochloride. This method utilizes metal reagents such as Grignard reagents or lithium reagents to perform nucleophilic addition to inert nitriles, followed by methanol quenching and subsequent salt formation to isolate stable NH imine hydrochloride. It is worth noting that this type of salt intermediate is highly sensitive to water. Through extensive optimization and screening, the team achieved the first efficient direct asymmetric hydrogenation of aryl-alkyl NH imine hydrochloride. Using an Ir-(S,S)-f-Binaphane catalyst combination, they achieved good enantioselectivity control at a catalyst dosage of 5 mol% and a hydrogen pressure of 1.01 MPa. Subsequently, Zhang Xumu's team further explored the direct asymmetric hydrogenation of diaryl-substituted NH imine hydrochloride. Using [Ir(COD)Cl]2 as a catalyst precursor, they screened different bisphosphine and monophosphine chiral ligands, ultimately finding that the (S)-N-Bn,N-Me-MonoPhos ligand provided the best enantioselectivity control. However, the substrate range was relatively limited; excellent enantioselectivity was achieved when one of the aryl groups had a substituent at the ortho position, while poor enantioselectivity was achieved when the ortho position was unsubstituent. In 2014, Zhang Xumu's team successfully achieved high enantioselectivity hydrogenation of NH imine hydrochloride under mild conditions using the Rh / Zhaophos catalytic system. Through NMR experiments, titration experiments, and other controlled experiments, it was hypothesized that the chloride anion in the substrate can bind to the thiourea structural unit in the ligand via hydrogen bonds, thereby achieving hydrogen transfer and enantioselectivity control of the reaction. Deuteration experiments confirmed that the reaction most likely involved direct reduction of the imine ion, rather than enamine reduction.

[0006] Although some progress has been made in the asymmetric catalytic hydrogenation of imine hydrochlorides, its substrate scope is significantly limited, and the substrates themselves are particularly sensitive to water and prone to decomposition. The use of strongly basic Grignard or lithium reagents in substrate synthesis makes it difficult for some base-sensitive groups to tolerate the reaction, and the reaction efficiency is also very limited, requiring a catalyst dosage of at least 1 mol%. Utilizing the in-situ reaction of ammonium salts with ketones to generate NH imines or their salts, followed by in-situ reduction, is undoubtedly a better option, greatly broadening the substrate versatility.

[0007] The exploration of asymmetric reductive amination involving ammonium salts originated in industry. In 2005, Takasago Corporation reported a one-step asymmetric reductive amination reaction using β-keto esters as substrates, NH4OAc as the amine source, and a chiral bisphosphine-Ru(OAc)2 complex as a catalyst to obtain chiral β-amino acid esters; in the same year, Bunlaksananusorn's group also reported a similar reaction. In 2009, scientists from Merck and Takasago explored an asymmetric reductive amination reaction using β-ketoamides as substrates, ammonium salts as the amine source, and chiral bisphosphine-Ru complexes as catalysts, producing chiral β-aminoamides with good substrate universality and achieving high yields (81%–96%) and enantioselectivity (>94% ee). More importantly, the best-selling drug sitagliptin can be synthesized in one step using this method with a yield of 91% and an ee value as high as 99.5%. Subsequently, chiral bisphosphine-Ru complex systems have also been reported to be used to catalyze the reductive amination of other β-keto acid derivatives, with the corresponding products being directly converted into key drug intermediates.

[0008] Inspired by the above work, Zhang Xumu's team explored a more challenging reaction that simultaneously achieves dynamic kinetic resolution and asymmetric reductive amination. The reaction uses racemic α-acyl-lactams as substrates, NH4OAc as the amine source, hydrogen as the reducing agent, and (S)-Segphos-Ru(OAc)2 as the catalyst to synthesize β-aminolactams containing two consecutive chiral centers in one step. For some cyclic lactam substrates, the reaction achieves good yields (up to 98%), excellent enantioselectivity (up to 99% ee), and diastereoselectivity (dr > 20:1). The products prepared using this method can be readily converted into key intermediates for fluoroquinolone prodrugs.

[0009] Early reports primarily focused on β-keto acid derivatives as substrates, mainly because these substrates rapidly generate stable β-NH₂ dehydrogenated amino acid derivatives with ammonium salts. Furthermore, these derivatives readily isomerize to relatively stable imine isomers under acidic conditions, allowing imine reduction to dominate the competition with direct ketone reduction. In addition, the double chelation of chiral metals with NH imines and ester or amide carbonyl groups provides a favorable chiral environment, which is beneficial for enantioselective control of the reaction.

[0010] Asymmetric reductive amination between simple arylalkyl ketones and ammonium salts can directly construct chiral primary benzylamines in one step, which are key intermediates for many drugs such as cinacalcet and rivastigmine. However, the lack of a suitable catalytic system to simultaneously ensure high reactivity and high enantioselectivity has long been a challenge for this reaction. As early as 2003, Kadyrov's group reported the asymmetric hydrogen transfer reductive amination of simple ketones such as acetophenone and naphthyl acetophenone, using ammonium formate as both a hydrogen source and an amine source, achieving an ee value of over 95% for the product. However, the reaction inevitably produced a large amount of formylated byproducts, requiring a hydrolysis step to obtain a satisfactory yield of chiral primary amines. In 2018, Zhang Xumu and Yin Qin's team explored the asymmetric reductive amination of simple arylalkyl ketones using ammonium acetate as the amine source and hydrogen as the reducing agent, finding the (R)-DTBM-C3-TunePhos-Ru(OAc)2 complex to be the optimal catalyst. Under optimal conditions, acetophenone substrates can be readily converted to the corresponding chiral primary amines, with yields reaching up to 96% and ee values ​​up to 97%. The reaction has a wide substrate applicability; electron-pulling and electron-withdrawing groups on the aryl group do not affect the smooth progress of the reaction. Unfortunately, the catalytic effect of this system on alkyl-alkyl ketones is not satisfactory, with poor yields and enantioselectivity of the corresponding chiral aliphatic primary amines. In the same year, researchers at BASF in Germany also reported a similar reaction. However, they used ammonia, a more industrially preferred amine source, and a combination of RuHCl(CO)(PPh3)3 and (S,S)-f-binaphane as catalysts. The enantioselectivity of the reaction products reached a maximum of 87% ee. This system also showed poor catalytic effect on simple alkyl-alkyl ketones and diaryl ketones.

[0011] In 2020, Zhang Xumu and Yin Qin's team explored and achieved the first highly enantioselective asymmetric reductive amination of diaryl ketones. Using NH4OAc as the amine source, (S)-Segphos-Ru(OAc)2 as the catalyst, and hydrogen as the reducing agent, the reaction can synthesize chiral primary diarylmethylamines in one step. The authors cleverly utilized the neighboring group assist effect, introducing an ortho-hydroxyl group into the substrate molecule to form an intramolecular hydrogen bond with the imine intermediate, accelerating and stabilizing the imine intermediate. Simultaneously, the intramolecular hydrogen bond ensures that the imine intermediate exists almost entirely in the E configuration, providing a rigid chiral environment for asymmetric catalysis, thereby significantly improving the enantioselectivity of the reaction. Under optimal catalytic conditions, the yield of chiral diarylmethylamines can reach 97%, with an ee value greater than 99%. Prior to this, the direct asymmetric reductive amination of diaryl ketones was extremely challenging. Besides the common difficulties of reductive amination reactions mentioned earlier, other challenges included: (1) compared to simple aryl alkyl ketones, decreased electrophilicity and increased steric hindrance made imine formation difficult; (2) the Z / E isomer tautomerism of the imine resulted in poor enantioselectivity control; and (3) the close steric hindrance of the two aryl groups made chiral recognition difficult. In 2022, Zhang Xumu and Yin Qin's team reported the asymmetric reductive amination of α-acetal-substituted ketones, producing chiral α-aminoacetal products. Ultimately, through condition optimization, the aryl-substituted products achieved good yields with a maximum ee greater than 99%. These products can be easily converted into important chiral fragments such as chiral amino acids and amino alcohols. In 2022, the team also reported a one-step synthesis of highly optically pure α-aminoamides using α-ketoamides as substrates via asymmetric reductive amination. Both α-aryl-substituted and α-alkyl-substituted ketoamides yielded good results, with 42 examples showing an ee of up to 99%. While asymmetric biomimetic transamination of α-keto acids or ketone esters can also effectively yield α-amino acids or their derivatives, this strategy is currently limited to the highly enantioselective synthesis of α-alkyl-substituted amino acids. The method developed by Zhang Xumu and Yin Qin's team overcomes the limitations of asymmetric biomimetic transamination in terms of substrate scope and complements biocatalysis. Notably, the enantiomeric α-aminoamide product obtained can be successfully hydrolyzed under hydrochloric acid reflux to yield chiral α-amino acids while maintaining optical purity, providing a new approach for the preparation of chiral non-natural amino acids.

[0012] Although asymmetric reductive amination reactions involving ammonium salts under hydrogen reducing conditions have seen some development and a broader substrate range, they face the problem of limited catalytic systems: most current reports on this type of reaction use the same type of catalyst, namely chiral bisphosphine-Ru(OAc)2 complexes. Despite the wide variety of chiral bisphosphine ligands, current results show that ruthenium catalysts formed by these ligands struggle to handle some challenging substrates, such as alkyl-alkyl ketones and α-keto acids (esters). More importantly, the efficiency of chiral bisphosphine-Ru(OAc)2 complexes in catalyzing asymmetric reductive amination of ketones is extremely limited, with TON values ​​mostly less than 500, and most reports using a catalyst dosage of 1 mol%, further restricting the application of this system in practical production. Hydrogen transfer reactions, due to their avoidance of hydrogen gas and the use of small-molecule organic compounds such as formic acid and isopropanol as hydrogen sources, the absence of autoclaves, mild conditions, and simple operation, have attracted increasing attention.

[0013] In 2013, Xiao Jianliang's team reported the hydrogen transfer reductive amination of ketones catalyzed by Cp*Ir(III) complexes based on imine anion ligands. Under optimized conditions, using a 5:2 formic acid / triethylamine azeotrope as the hydrogen source, 0.1 mol% iridium complex as the catalyst, and ammonium formate as the amine source, various types of ketones could be successfully converted into their corresponding racemic amine compounds. This type of catalyst has a very wide substrate applicability; aliphatic ketones and α-keto acids (esters) that could not achieve satisfactory results using ruthenium catalysis systems can all be well converted using this type of catalyst. In light of this, in 2019, Cramer's team replaced the pentamethylcyclopentadiene anion ligand (Cp*) in this type of iridium complex with a chiral cyclopentadiene anion ligand and successfully achieved the asymmetric hydrogenation of oximes using it as a catalyst. The product, chiral hydroxylamine, achieved an ee value of over 96% and a TON of up to 4000, meaning the catalyst loading was only 0.025 mol%.

[0014] In summary, developing chiral primary amine catalysts and reaction systems with a wider substrate range, higher efficiency, and better enantioselectivity control remains a key research focus and challenge in this field. Summary of the Invention

[0015] The purpose of this application is to provide a novel chiral iridium complex, its preparation method, and its application.

[0016] To achieve the above objectives, this application adopts the following technical solution:

[0017] One aspect of this application discloses a chiral iridium complex, which has the structure shown in structural formula 1;

[0018]

[0019] Wherein, X is a halogen or sulfonate group, and R, R1, R2, R3, R4, R5, and R6 are independently selected from methyl, ethyl, methoxy, ethoxy, N,N-dimethyl, n-propyl, isopropyl, tert-butyl, trifluoromethyl, phenyl, substituted phenyl, and halogen. Among them, halogens include, for example, fluorine, chlorine, bromine, and iodine.

[0020] This application presents the first chiral iridium complex based on a pyridine carboxamide anion ligand. This chiral iridium complex can be used to catalyze asymmetric reductive amination and asymmetric hydrogen transfer reductive amination reactions, enabling one-step synthesis of chiral primary amines from ketone substrates. It exhibits advantages such as high catalytic efficiency and good enantioselectivity control. Compared to bisphosphine-ruthenium complex catalytic systems, this chiral iridium complex offers advantages such as a wider substrate applicability and higher catalytic activity. Furthermore, it is more stable in air and can even be stored directly in air. This application develops a novel class of catalysts, providing a new approach to the design of asymmetric reductive amination catalysts. It breaks the long-standing limitation of having only one catalytic system for the synthesis of chiral primary amines using asymmetric reductive amination reactions, laying the foundation for the industrial synthesis of asymmetric reductive amination reactions and chiral primary amines.

[0021] In one implementation of this application, X is Cl, I, or OMs.

[0022] In this context, "OMs" stands for "-O-Ms", and "Ms" stands for methyl sulfone.

[0023] In one implementation of this application, the chiral iridium complex is at least one of complex 1, complex 1a, and complex 2 to complex 16;

[0024]

[0025] It should be noted that the above-mentioned 17 chiral CpIr(III) complexes based on pyridine carboxamide anion ligands, namely complex 1, complex 1a, complex 2 to complex 16, are only 17 complexes specifically synthesized in one implementation of this application. It can be understood that under the inventive concept of this application, more chiral CpIr(III) complexes based on pyridine carboxamide anion ligands can be synthesized, not limited to the above 17.

[0026] Another aspect of this application discloses the use of the chiral iridium complex of this application as a catalyst for asymmetric reductive amination or asymmetric hydrogen transfer reductive amination.

[0027] Another aspect of this application discloses a catalyst for an asymmetric reductive amination reaction or an asymmetric hydrogen transfer reductive amination reaction, the catalyst containing the chiral iridium complex of this application.

[0028] It should be noted that the key aspect of this application lies in the pioneering development of a novel chiral CpIr(III) complex based on a pyridinecarboxamide anion ligand as a catalyst for asymmetric reductive amination or asymmetric hydrogen transfer reductive amination reactions. Therefore, the chiral iridium complex of this application can be used as a catalyst for asymmetric reductive amination or asymmetric hydrogen transfer reductive amination reactions.

[0029] Another aspect of this application discloses a method for preparing chiral primary amines using an asymmetric reductive amination reaction or an asymmetric hydrogen transfer reductive amination reaction, the method comprising using the chiral iridium complex of this application as a catalyst.

[0030] In one implementation of this application, the method for preparing a chiral primary amine using an asymmetric reductive amination reaction or an asymmetric hydrogen transfer reductive amination reaction includes a catalytic reaction using a ketone as a substrate in a solvent containing an amine source and a hydrogen source. The specific catalytic reaction is as follows.

[0031]

[0032] The catalyst is a chiral iridium complex of this application, and R7 and R8 are independently selected from phenyl, substituted phenyl, methyl, tert-butyl, ester, carboxylic acid, cyclohexyl, tert-butyl, tert-pentyl, and adamantyl.

[0033] In one implementation of this application, the amine source is at least one selected from ammonium formate, ammonium acetate, ammonium salicylate, ammonium fluoride, ammonium chloride, ammonium sulfate, and ammonia.

[0034] In one implementation of this application, the hydrogen source is at least one of hydrogen gas, formic acid, and isopropanol.

[0035] In one implementation of this application, the solvent is at least one selected from methanol, ethanol, isopropanol, tert-butanol, tert-amyl alcohol, 2,2,2-trifluoroethanol, 1,1,1,3,3,3-hexafluoroisopropanol, tetrahydrofuran, toluene, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, and N-methylpyrrolidone.

[0036] In one implementation of this application, the reaction system also contains additives.

[0037] In one implementation of this application, the additive is AgOTf.

[0038] It should be noted that the additive AgOTf is not mandatory in the catalytic reactions of this application; it is only required in certain reactions. For example, in one implementation of this application, when K7 is used as the substrate and complexes 1, 2, 3, 4, 5, 6, 10, or 15 are used as catalysts, 2.5 mol% AgOTf needs to be added.

[0039] In one implementation of this application, the ketone is at least one of K1 to K15;

[0040]

[0041] It should be noted that the 15 ketones K1 to K15 are only one implementation method of this application, specifically using the substrates; it can be understood that under the inventive concept of this application, more ketones can be catalyzed into corresponding chiral primary amines, not limited to the above 15 ketones.

[0042] Another aspect of this application discloses a method for preparing the chiral iridium complex of this application, including preparing the chiral iridium complex of this application by at least one of the following methods;

[0043] Method 1 includes the use of chiral iridium dimer compounds [Ir (OMe) The chiral iridium complex of this application was prepared by heating Cp*I2]2, amide ligand and K2CO3 in p-xylene under reflux;

[0044] Method 2 includes the use of chiral iridium dimer compounds [Ir (OMe) The chiral iridium complex of this application was prepared by heating imine ligand and sodium acetate in 1,2-dichloroethane under reflux.

[0045] In one implementation of this application, the reflux temperature is 80-140℃ and the reaction time is 20-28h.

[0046] In one implementation of this application, method one further includes dissolving the iodinated product in dichloromethane, then adding AgOTf, and reacting at room temperature to obtain a chiral iridium complex where X is Cl. The iodinated product is the chiral iridium complex prepared by method one, such as complex 1, which further yields a chiral iridium complex where X is Cl, such as complex 1a.

[0047] Due to the adoption of the above technical solutions, the beneficial effects of this application are as follows:

[0048] The chiral iridium complexes of this application can be used as catalysts for asymmetric reductive amination and asymmetric hydrogen transfer reductive amination reactions, catalyzing the one-step synthesis of chiral primary amines from ketone substrates. They possess advantages such as a wide substrate applicability and high catalytic activity. Furthermore, the chiral iridium complexes of this application exhibit good stability in air and can be stored directly in air. These chiral iridium complexes provide a new scheme and route for the synthesis of chiral primary amines via asymmetric reductive amination reactions, laying the foundation for the industrial synthesis of asymmetric reductive amination reactions and chiral primary amines. Attached Figure Description

[0049] Figure 1 This is a single-crystal structure diagram of coordination compound 1a in the embodiments of this application. Detailed Implementation

[0050] The present invention will now be described in further detail with reference to specific embodiments and accompanying drawings. In the following embodiments, many details are described to facilitate a better understanding of the present application. However, those skilled in the art will readily recognize that some features may be omitted in different situations, or may be replaced by other materials or methods. In some cases, certain operations related to the present application are not shown or described in the specification. This is to avoid obscuring the core parts of the present application with excessive description. For those skilled in the art, detailed description of these related operations is not necessary; the relevant operations can be fully understood based on the description in the specification and general technical knowledge in the art.

[0051] Furthermore, the features, operations, or characteristics described in the specification can be combined in any suitable manner to form various embodiments. At the same time, the steps or actions in the method description can be rearranged or adjusted in a manner obvious to those skilled in the art. Therefore, the various orders in the specification and drawings are only for the clear description of a particular embodiment and do not imply a necessary order, unless otherwise stated that a particular order must be followed.

[0052] The serial numbers assigned to structural formulas or functional groups in this application, such as “Structural Formula 1”, “Coordination Compound 1”, “Coordination Compound 1a”, “Coordination Compound 2”, “R1”, “R2”, “R3”, “K1”, “K15”, etc., are used only to distinguish the described objects and have no sequential or technical meaning.

[0053] Terminology Explanation:

[0054] In this application, "room temperature" means 25℃±2℃.

[0055] In this application, “[Ir (OMe) Cp*I2]2” represents a chiral iridium dimer compound.

[0056] In this application, AgOTf represents silver trifluoromethanesulfonate.

[0057] In this application, Me represents methyl and OMe represents methoxy.

[0058] In this application, Ph represents phenyl.

[0059] Inspired by existing technologies, this application explores hydrogen transfer reductive amination reactions catalyzed by ammonium formate as both an amine source and a reducing agent, and chiral CpIr(III) complexes as catalysts. The aim is to broaden the substrate range, improve reaction efficiency, and reduce catalyst usage. This application attempts to introduce chiral fragments into the CpIr(III) catalyst, including introducing chirality onto the Cp backbone or using chiral bidentate auxiliary ligands. The resulting CpIr(III) catalyst exhibits significantly improved and expanded activity and substrate applicability compared to the bisphosphine-Ru(OAc)2 system, and the asymmetric reductive amination ee value can reach 70%. The chiral iridium complex of this application provides a new scheme and route for the synthesis of chiral primary amines via asymmetric reductive amination reactions, laying the foundation for the industrial synthesis of asymmetric reductive amination reactions and chiral primary amines.

[0060] Example

[0061] I. Synthesis of Chiral Iridium Complexes

[0062] In this example, chiral iridium complexes were synthesized using the following methods:

[0063] Method 1, using chiral iridium dimer compounds [Ir (OMe) The chiral iridium complex in this example was prepared by heating Cp*I2]2, amide ligands, and K2CO3 in p-xylene under reflux.

[0064] Method 2, using chiral iridium dimer compounds [Ir (OMe) The chiral iridium complex in this example was prepared by heating imine ligands and sodium acetate in 1,2-dichloroethane under reflux.

[0065] Using the two methods described above, this example specifically synthesized 17 chiral iridium complexes, including complex 1, complex 1a, complex 2 to complex 16.

[0066]

[0067] The specific synthesis methods for the above 17 chiral iridium complexes are as follows: The technical route for synthesizing complex 1 is as follows:

[0068]

[0069] Specifically, under an argon atmosphere, a chiral iridium dimer [Ir(OMe)Cp*I2]2 (17.0 mg, 0.01 mmol), ligand L1 (4.6 mg, 0.02 mmol), and anhydrous K2CO3 (13.8 mg, 0.1 mmol) were added to a 10 mL Schlenk tube, followed by anhydrous p-xylene solvent (1.0 mL). The reaction was stirred at 140 °C for 24 h. After cooling to room temperature, p-xylene was removed by vacuum distillation. The residue was extracted with dichloromethane, filtered through diatomaceous earth, and the diatomaceous earth pad was washed three times with dichloromethane (2 mL × 3). The dichloromethane solutions were combined, evaporated to dryness, and the crude product was purified by column chromatography to obtain a yellow solid, namely complex 1, with an eluent ratio of DCM / MeOH of 100:1 to 50:1. The total yield of complex 1 was 11.0 mg, with a yield of 58% and a purity of over 95%.

[0070] Characterization data of coordination compound 1: 1 ¹H NMR (400MHz, CDCl₃) (The product obtained was a mixture of diastereomers in a ratio of 5:3; data correspond to the main isomer) δ 8.87 (d, J = 5.3 Hz, 1H), 8.21 (d, J = 7.0 Hz, 1H), 7.94 (d, J = 7.7 Hz, 1H), 7.76 (d, J = 8.1 Hz, 1H), 7.68 (d, J = 12.0 Hz, 1H), 7.49 (t, J = 7.0 Hz, 1H), 7.38–7.34 (m, 3H), 7.16 (s, 1H), 7.12–7.10 (m, 1H), 7.04–7.02 (m ,1H),6.95(s,1H),6.92-6.89(m,2H),6.83(d,J=8.2Hz,3H),5.93(d,J=8.5Hz,2H),5.39(t,J=2.2Hz,1H),5.23(s,1H),5.14(s,1H), 3.92(s,3H),3.83(t,J=8.0Hz,3H),3.67(d,J=15.1Hz,1H),3.46(s,3H),3.34(s,3H),2.65(d,J=14.2Hz,1H),2.48(d,J=16.0Hz,1H). 13C NMR (101MHz, CDCl3) δ168.46,156.45,155.86,155.29,155.21,155.15,154.93,150.91,139.91,138.15,138.04,137.83, 136.65,134.18,133.79,128.35,127.76,127.26,127.12,127.05,126.95,126.90,126.78,126.53,126.42,125.74,124. 82,124.43,124.17,113.85,112.26,106.48,106.13,105.77,105.65,102.78,94.46,91.25,87.59,84.34,78.83,77.36, 72.59,71.14,64.33,56.60,55.85,55.74,55.62,55.59,55.26,29.83,24.51,24.42,23.59,21.73.HRMS(ESI):calcd.for C 42 H 35 IIrN2O4 + [M+H] + =951.1271,found:951.1263;C 42 H 34 IrN2O4 + ,[MI]+=823.2148,found:823.2139.

[0071] It should be noted that the synthesis of metal complexes is much more difficult than that of simple organic compounds, and the reaction mechanism is also more complex. Generally, a yield of 60% is considered relatively high. In this example, the yield of complex 1 reached 58%, which is a relatively ideal result.

[0072] Based on coordination compound 1, coordination compound 1a was further synthesized. The synthetic route of coordination compound 1a is as follows:

[0073]

[0074] Specifically, under light-protected conditions, complex 1 was dissolved in dichloromethane, and then one equivalent of AgOTf was added. The mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction solution was filtered through diatomaceous earth, and the diatomaceous earth layer was washed with a 5:1 dichloromethane / methanol eluent until the filtrate was colorless. The filtrates were combined and evaporated to dryness to obtain complex 1a. The yield of complex 1a was 40%, and its purity was 95%.

[0075] Characterization data of coordination compound 1a: 1¹H NMR (600MHz, acetone-d6) (The product obtained was a mixture of diastereomers in a 5:1 ratio; data correspond to the main isomer) δ 9.25 (d, J = 5.4 Hz, 1H), 8.20 (t, J = 7.6 Hz, 1H), 8.13 (d, J = 7.5 Hz, 1H), 8.06 (d, J = 8.2 Hz, 1H), 7.86 (d, J = 8.2 Hz, 1H), 7.64 (t, J = 6.4 Hz, 1H), 7.54 (t, J = 6.0 Hz, 1H), 7.44 (d, J = 26.4 Hz, 3H), 7.37 (t, J = 7.5 Hz, 1H), 7.15 (t, J = 6.0 Hz, 1H) z,1H),7.06(t,J=6.0Hz,1H),6.85(d,J=6.0Hz,1H),6.77-6.74(m,3H),5 .98(s,1H),5.91(d,J=7.7Hz,2H),5.34(s,1H),5.15(s,1H),3.97(s,3H) ,3.69(d,J=15.0Hz,1H),3.43(s,3H),3.36(s,3H),2.71(d,J=14.1Hz,1H),2.35(d,J=15.0Hz,1H),1.75(d,J=14.1Hz,1H).HRMS(ESI):calcd.for C 42 H 35 ClIrN2O4 + [M+H] + =859.1915,found:859.1907;C 42 H 34 IrN2O4 + [MI] + =823.2148,found:823.2148.

[0076] The single-crystal structure diagram of coordination compound 1a is shown below. Figure 1 As shown, the single crystal of the test structure in this example was obtained by cooling and crystallization of a saturated acetone solution of complex 1a. Its structural diagram was obtained by acquiring single crystal data using a single-crystal diffractometer. Figure 1 The single-crystal structure characterization confirmed that the product indeed obtained the structure shown in Formula 1.

[0077]

[0078] Wherein, X is a halogen or sulfonate group, and R, R1, R2, R3, R4, R5, and R6 are independently selected from methyl, ethyl, methoxy, ethoxy, N,N-dimethyl, n-propyl, isopropyl, tert-butyl, trifluoromethyl, phenyl, substituted phenyl, and halogen. Wherein, the halogen is fluorine, chlorine, bromine, or iodine.

[0079] The synthesis methods of complexes 2 to 11 are similar to those of complex 1, using chiral iridium dimer compounds [Ir (OMe) [Cp*I2]2, amide ligands, and K2CO3 were prepared by heating under reflux in p-xylene. Characterization data for complexes 2 to 11 are as follows:

[0080] Characterization data of coordination compound 2: 1 ¹H NMR (600MHz, CDCl₃) (diastereomeric mixture, 5:1 ratio, data correspond to the main isomer) δ 8.90 (d, J = 5.4Hz, 1H), 8.22–8.20 (m, 1H), 7.96 (td, J = 7.7, 1.2Hz, 1H), 7.88 (d, J = 8.2Hz, 1H), 7.76 (d, J = 8.2Hz, 1H), 7.43 (t, J = 7.5Hz, 1H), 7.37–7.36 (m, 2H), 7.29 (s, 1H), 7.17 (s, 1H), 7.09–7.03 (m, 3H), 6.9 3(d,J=8.5Hz,1H),6.82(d,J=8.4Hz,1H),6.70(s,1H),5.52(t,J=2.2Hz,1H),5.16(t,J=2.2Hz,1H),4.94(s,1H),3.91(s,3H),3.6 7(d,J=15.2Hz,1H),3.46(s,3H),3.26(s,3H),2.56(d,J=14.3Hz,1H),2.50(d,J=15.2Hz,1H),1.94(d,J=14.2Hz,1H),1.64(s,6H). 13 C NMR (101MHz, CDCl3) δ168.38,156.58,155.29,155.02,150.90,138.15,138.00,136.50,133.95,133.77,130.59,1 29.35,127.69,127.35,127.31,127.09,126.98,126.93,126.88,126.74,126.54,126.39,126.08,125.98,124.64, 124.46,124.12,106.41,106.13,105.88,105.62,103.89,91.49,89.04,87.80,82.57,78.80,77.36,75.91,68.84, 64.46,59.84,59.57,56.53,55.85,55.80,55.66,24.61,24.49,23.62,21.98,16.57,15.45.HRMS(ESI):calcd.for C44 H 39 IIrN2O4 + [M+H] + =979.1584,found:979.1574;C 44 H 38 IrN2O4 + [MI] + =851.2461, found:851.2452. Complex 2 is a yellow solid with a yield of 41% and a purity of 95%.

[0081] Characterization data of complex 3: 1 H NMR (600MHz, Methanol-d4) δ7.97(d,J=8.2Hz,1H),7.87(t,J=6.0Hz,1H),7.81(d,J=8.3Hz,1H),7.51(d,J=7 .2Hz,1H),7.45(t,J=7.5Hz,1H),7.41(s,1H),7.35-7.33(m,2H),7.10-7.01(m,4H),6.82-6.79(m,3H),6.06( The chromatogram values ​​are as follows: 5.54(s,1H), 4.94(s,1H), 3.94(s,3H), 3.72(d,J=15.2Hz,1H), 3.42(s,3H), 3.41(d,J=15.0Hz,1H), 3.37(s,3H), 3.30(s,3H), 2.49(d,J=14.0Hz,1H), 2.33(d,J=15.2Hz,1H), 1.88(d,J=14.1Hz,1H), 1.61(s,6H). Complex 3 is a yellow crystal with a yield of 25% and a purity of 95%. Its crystalline form is poorly soluble in most organic solvents. The starting materials were completely consumed during the synthesis of complex 3. The low yield may be due to some products being adsorbed onto the diatomaceous earth and not eluted. Further optimization can improve the yield.

[0082] Characterization data of coordination compound 4: 1¹H NMR (400MHz, CDCl₃) (diastereomeric mixture, 2:1 ratio, data correspond to the main isomer) δ 7.95 (t, J = 7.8Hz, 1H), 7.89 (d, J = 7.0Hz, 1H), 7.76 (d, J = 8.3Hz, 2H), 7.65 (s, 1H), 7.40–7.32 (m, 3H), 7.16 (d, J = 4.8Hz, 2H), 7.09–6.95 (m, 4H), 6.78 (d, J = 8.4Hz, 1H) The hydroxyl groups (d, J = 15.3 Hz, 1H) were 5.80 (s, 1H), 5.44 (s, 1H), 4.75 (s, 1H), 4.17 (s, 3H), 3.89 (s, 3H), 3.72 (d, J = 15.3 Hz, 1H), 3.45 (s, 3H), 3.23 (s, 3H), 2.52 (d, J = 15.3 Hz, 1H), 2.36 (d, J = 14.0 Hz, 1H), 2.06 (d, J = 14.0 Hz, 1H), 1.45 (s, 9H), and 1.26 (s, 9H). Complex 4 was a yellow solid with a yield of 55% and a purity of 95%.

[0083] Characterization data of coordination compound 5: 1 H NMR (400MHz, CDCl3) δ7.85 (d, J = 6.3Hz, 2H), 7.82-7.76 (m, 3H), 7.46-7.35 (m, 2H), 7.1 7-7.02(m,4H),6.99-6.96(m,1H),6.90-6.86(m,2H),6.74(s,1H),6.47(s,1H),6.24( The chromatogram values ​​are: s, 1H; 4.46(s, 1H); 3.98(s, 3H); 3.77(d, J = 12.5 Hz, 2H); 3.33(d, J = 12.9 Hz, 1H); 3.22(s, 3H); 2.73(s, 3H); 2.43(s, 3H); 2.39-2.30(m, 4H, -CH3+CHHoverlap); 2.28(s, 3H). Complex 5 is a yellow solid with a yield of 42% and a purity of 95%.

[0084] Characterization data of coordination compound 6: 1¹H NMR (600MHz, CDCl₃) (diastereomeric mixture, 2:1 ratio, data correspond to the main isomer) δ 8.06 (d, J = 7.2Hz, 1H), 7.92–7.86 (m, 3H), 7.78 (d, J = 8.2Hz, 1H), 7.68 (t, J = 6.0Hz, 2H), 7.53–7.51 (m, 2H), 7.47–7.41 (m, 2H), 7.38 (t, J = 6.0Hz, 1H), 7.15 (s, 1H), 7.12–7.06 (m, 2H) The chromatogram values ​​are as follows: 7.02-6.98 (m, 2H), 6.96 (d, J = 8.4 Hz, 1H), 6.58 (s, 1H), 6.35 (d, J = 7.1 Hz, 1H), 5.83 (s, 1H), 4.52 (s, 1H), 4.20 (s, 1H), 3.96 (s, 3H), 3.88 (d, J = 15.4 Hz, 2H), 3.81 (s, 3H), 3.15 (d, J = 13.7 Hz, 1H), 3.03 (s, 3H), 2.43 (d, J = 15.0 Hz, 1H). Complex 6 is a yellow solid with a yield of 20% and a purity of 95%. The low yield of complex 6 is attributed to incomplete conversion of the starting material; further optimization could improve the yield.

[0085] Characterization data of coordination compound 7: 1 ¹H NMR (400MHz, CDCl₃) (diastereomeric mixture, ratio 5:2, data correspond to the main isomer) δ 7.98 (t, J = 7.9Hz, 1H), 7.90–7.88 (m, 1H), 7.77 (d, J = 8.2Hz, 2H), 7.39–7.34 (m, 3H), 7.22 (s, 1H), 7.18 (s, 1H), 7.11 (s, 1H), 7.05–7.02 (m, 3H), 6.95–6.86 (m, 3H), 6.65 (s, 1H) The concentrations of ions were: 5.70 (t, J = 4.4 Hz, 1H), 5.54 (s, 1H), 4.79 (s, 1H), 4.17 (s, 3H), 3.69 (d, J = 6.0 Hz, 1H), 3.65 (s, 3H), 3.26 (s, 3H), 3.22 (s, 6H), 2.65 (d, J = 14.1 Hz, 1H), 2.48 (d, J = 15.2 Hz, 1H), and 2.30 (d, J = 14.0 Hz, 1H). Complex 7 was a yellow solid with a yield of 41% and a purity of 95%.

[0086] Characterization data of coordination compound 8: 1¹H NMR (600MHz, CDCl₃) δ (diastereomeric mixture, ratio 3:1, data correspond to the main isomer) 7.96 (t, J = 7.9Hz, 1H), 7.87 (d, J = 7.5Hz, 1H), 7.77 (t, J = 7.5Hz, 2H), 7.40–7.33 (m, 2H), 7.18 (d, J = 15.6Hz, 2H), 7.06–7.02 (m, 3H), 6.90 (d, J = 8.5Hz, 1H), 6.85 (d, J = 8.4Hz, 1H), 6.70–6.63 (m, 2H), 5.71 (s, 1H), 5.51 ( The q values ​​are: s, 1H; 4.77(s, 1H); 4.17(s, 3H); 4.06(dt, J = 13.8, 7.0 Hz, 1H); 3.89(s, 3H); 3.84(q, J = 6.4 Hz, 2H); 3.69–3.47(m, 4H); 3.24(s, 3H); 2.66(d, J = 14.3 Hz, 1H); 2.47(d, J = 15.1 Hz, 1H); 2.31(d, J = 14.3 Hz, 1H); 1.29–1.26(m, 3H); 1.23–1.20(m, 6H). Complex 8 is a yellow solid with a yield of 53% and a purity of 95%.

[0087] Characterization data of coordination compound 9: 1 ¹H NMR (600MHz, CDCl₃) (diastereomeric mixture, ratio 4:1, data correspond to the main isomer) δ 7.94 (t, J = 7.8Hz, 1H), 7.89 (d, J = 7.2Hz, 1H), 7.86 (d, J = 8.1Hz, 1H), 7.76 (d, J = 8.2Hz, 1H), 7.41 (t, J = 7.3Hz, 1H), 7.35 (t, J = 7.8Hz, 1H), 7.29 ( The chromatogram values ​​are as follows: 7.15(s, 1H), 7.04(t, J = 7.5 Hz, 2H), 7.00-6.89(m, 4H), 6.79(d, J = 8.4 Hz, 1H), 5.56(d, J = 3.0 Hz, 2H), 4.92(s, 1H), 4.14(s, 3H), 3.88(s, 3H), 3.64(d, J = 15.2 Hz, 1H), 3.47-3.44(m, -OCH3+CHH overlap, 4H), 3.32(s, 3H), 2.73-2.69(m, 1H), 2.52-2.28(m, 4H), 1.90(d, J = 14.2 Hz, 1H), 0.94(m, 6H). Complex 9 is a yellow solid with a yield of 53% and a purity of 95%.

[0088] Characterization data of coordination compound 10: 1¹H NMR (600MHz, CDCl₃) (diastereomeric mixture, ratio 8:1, data correspond to the main isomer) δ 7.92–7.87 (m, 4H), 7.75 (d, J = 8.2 Hz, 1H), 7.43–7.40 (m, 1H), 7.36–7.33 (m, 2H), 7.16 (s, 1H), 7.05–7.02 (m, 2H), 6.96–6.93 (m, 3H), 6.81 (d, J = 8.4 Hz, 1H), 6.00 (s, 1H), 5.35 (q, J = 2.3 Hz, 1H), 5.03 (s, 1H), 4 .55-4.52(m,1H),4.29-4.27(m,1H),3.91(s,3H),3.79-3.76(m,1H),3.63(d,J=15.2Hz,1H),3.44(s,3H),3.43(s,3H),3.37(s,3 H),2.52(d,J=14.2Hz,1H),2.40(d,J=15.2Hz,1H),2.35-2.29(m,1H),1.86(d,J=14.2Hz,1H),1.62(s,6H).HRMS(ESI):calcd.for C 47 H 45 IIrN2O6 + [M+H] + =1053.1952,found:1053.1953;C 47 H 44 IrN2O6 + [MI] + =925.2829, found:925.2829. Complex 10 is a yellow solid with a yield of 21% and a purity of 95%. The low yield of Complex 10 is thought to be due to incomplete conversion of the raw materials; further optimization could improve the yield.

[0089] Characterization data of coordination compound 11: 1H NMR (400MHz, CDCl3) δ8.02(s,2H),7.98(t,J=12.0Hz,1H),7.92-7.90(m,1H),7.86(d,J=8.1Hz,1H),7.75(d,J=8.2Hz,1H),7.43(t,J=7.1 Hz,1H),7.36(t,J=7.5Hz,1H),7.33(s,1H),7.18(s,1H),7.16(s,1H),7.05-7.01(m,2H),6.96(d,J=8.0Hz,1H),6.75(d,J=8.3Hz,1H),6. 05(d,J=4.2Hz,1H),5.48(t,J=4.2Hz,1H),5.10(s,1H),4.55(t,J=7.8Hz,1H),4.31(d,J=10.1Hz,1H),3.98-3.96(m,1H),3.92(s,3H),3. 81-3.78(m,1H),3.66(d,J=15.2Hz,1H),3.44(s,3H),3.40(s,3H),2.63(d,J=13.6Hz,1H),2.44(d,J=15.2Hz,1H),1.68(d,J=13.5Hz,1H). 19 F NMR (376MHz, CDCl3) δ -62.63 (minor), -62.92 (major). Complex 11 is a yellow solid with a yield of 31% and a purity of 95%.

[0090] The synthesis methods for complexes 12-16 are consistent, consisting of chiral iridium dimer compounds [Ir (OMe) [Cp*I2]2, imine ligands, and sodium acetate were prepared by heating under reflux in 1,2-dichloroethane. Taking complex 12 as an example, its synthetic route is as follows:

[0091]

[0092] Specifically, under an argon atmosphere, a chiral iridium dimer compound [Ir] was added to a 10 mL Schlenk tube. (OMe)Cp*I₂]₂ (34.0 mg, 0.02 mmol), imine ligand L₁₂ (13.0 mg, 0.045 mmol), and NaOAc (32.8 mg, 0.4 mmol) were added, followed by anhydrous dichloroethane (1.0 mL). The reaction was stirred at 80 °C for 24 h. After cooling to room temperature, dichloroethane was removed by vacuum distillation. The residue was extracted with dichloromethane, filtered through diatomaceous earth, and the diatomaceous earth pad was washed three times with dichloromethane (2 mL × 3). The dichloromethane solutions were combined, evaporated to dryness, and the crude product was purified by column chromatography [eluent: PE / EA = 10:1 (V / V)] to give complex 12, yield: 14.7 mg (46%), reddish-brown solid, purity 95%.

[0093] Characterization data of coordination compound 12: 1 H NMR (400MHz, CDCl3) δ8.16(s,1H),8.08(s,1H),7.91(d,J=8.1Hz,1H),7.81(d,J=8.2Hz,1H),7.74(d,J=8.2Hz,1H),7.69(d,J=8.2Hz,1H),7.50(d ,J=7.6Hz,1H),7.47(d,J=4.1Hz,1H),7.43(d,J=7.1Hz,1H),7.31(dd,J= 17.0,8.1Hz,2H),7.26(s,1H),7.17(s,1H),7.11(d,J=8.1Hz,1H),7.08( s,1H),6.99(t,J=7.6Hz,1H),6.90(d,J=8.3Hz,1H),6.80(d,J=8.4Hz,1H ),6.54-6.45(m,1H),5.29(t,J=4.0Hz,1H),5.19(s,1H),5.14(s,1H),3. 95(s,3H),3.59(d,J=14.7Hz,1H),2.95(s,3H),2.82(d,J=14.0Hz,1H),2 .67(s,6H),2.48(s,3H),2.38(d,J=14.6Hz,1H),1.75(d,J=13.9Hz,1H).

[0094] Characterization data of complex 13: 1H NMR (600MHz, CDCl3) δ7.76(d,J=8.2Hz,1H),7.64(d,J=8.2Hz,1H),7.43-7.40(m,J=7.1Hz,4H),7.37-7.30(m,6H),7.18( s,1H),7.09-6.99(m,4H),6.88(d,J=8.4Hz,1H),6.76(s,1H),6.62(s,1H),6.54(s,1H),5.13(d,J=8.7Hz,1H),5.00(d,J= The concentrations of ions were: 8.6 Hz (1H), 4.48 (s, 1H), 4.08 (s, 3H), 3.93 (s, 3H), 3.89 (s, 3H), 3.88 (s, 3H), 3.66–3.56 (d, J = 12.5 Hz, 2H), 3.47 (d, J = 13.6 Hz, 1H), 3.34 (d, J = 12.9 Hz, 1H), 2.95 (s, 3H), 2.41 (d, J = 11.9 Hz, 1H), and 1.65 (t, J = 12.0 Hz, 1H). Complex 13 was a brown solid with a yield of 63% and a purity of 95%.

[0095] Characterization data of complex 14: 1 ¹H NMR (600MHz, CDCl₃) (diastereomeric mixture, 3:1 ratio, data correspond to the main isomer) δ 7.79 (d, J = 8.3Hz, 1H), 7.74 (d, J = 8.2Hz, 1H), 7.45 (d, J = 7.4Hz, 2H), 7.37–7.29 (m, 10H), 7.18 (s, 1H), 7.04–7.00 (m, 2H), 6.95 (d, J = 8.3Hz, 1H). J = 8.4 Hz, 1H), 6.87 (d, J = 8.5 Hz, 1H), 6.66 (s, 1H), 6.50 (s, 1H), 5.07 (d, J = 6.9 Hz, 1H), 4.98 (d, J = 6.9 Hz, 1H), 4.65 (s, 1H), 4.00 (s, 3H), 3.98 (d, J = 6.0 Hz, 2H), 3.96-3.93 (m, 4H, OCH3+CHH overlap), 3.81 (d, J = 5.6 Hz, 1H), 3.79 (s, 3H), 3.76 (s, 3H), 3.34-3.33 (m, OCH3+CHH overlap, 4H), 2.90 (d, J = 15.1 Hz, 1H). Complex 14 is a brown solid with a yield of 31% and a purity of 95%.

[0096] Characterization data of coordination compound 15: 1H NMR (600MHz, CDCl3) δ8.60 (d, J=2.4Hz, 1H), 7.73 (dd, J=8.1, 4.0Hz, 2H), 7.34-7 .31(m,2H),7.14(s,1H),7.01(ddd,J=8.1,6.8,1.2Hz,1H),6.99(s,1H),6.96-6. 91(m,2H),6.86(d,J=7.9Hz,1H),6.76(dd,J=16.5,8.2Hz,2H),6.15(s,1H),5.8 1(d,J=2.3Hz,1H),5.52(t,J=2.3Hz,1H),4.78(s,1H),4.23-4.20(m,1H),4.18-4 0.15(m,1H), 3.91(s,3H), 3.76-3.72(m,3H), 3.47(s,3H), 3.39(s,3H), 3.11(s,3H), 2.93-2.80(m,4H), 2.50(d,J=13.6Hz,1H), 2.40(d,J=14.9Hz,1H), 1.94(d,J=13.6Hz,1H), 1.89-1.85(d,J=4.1Hz,1H), 1.75-1.71(m,1H), 1.50(s,9H), 0.97(d,J=6.7Hz,1H), 0.86(d,J=7.0Hz,1H), 0.65(s,9H). Complex 15 is a reddish-brown solid with a yield of 59% and a purity of 95%.

[0097] Characterization data of complex 16: 1H NMR (600MHz, CDCl3) δ7.84(d,J=8.2Hz,1H),7.70(d,J=8.2Hz,1H),7.56(br.s,1 H),7.38(ddd,J=8.5,6.6,1.2Hz,1H),7.30(ddd,J=8.1,6.8,1.2Hz,1H),7.11(d ,J=9.2Hz,2H),7.00(ddd,J=8.2,6.8,1.2Hz,1H),6.97(ddd,J=8.3,6.8,1.2Hz, 1H),6.85(d,J=7.8Hz,2H),6.77(d,J=8.0Hz,1H),6.70(d,J=8.5Hz,1H),6.44(s, 1H),5.95(t,J=2.0,1.6Hz,1H),5.88(s,1H),5.26(s,1H),5.03(s,1H),4.20(dt ,J=10.3,5.0Hz,1H),4.08-4.00(m,1H),3.90(s,3H),3.77–3.72(m,2H),3.44(s Complex 16 is a yellow powder with a yield of 60% and a purity of 95%. The sine bars are: 3.40 (s, 3H), 3.29–3.23 (m, 4H), 2.92–2.51 (m, 6H), 2.36 (s, 3H), 2.20 (s, 3H), 1.97–1.86 (m, 2H), 1.80–1.70 (m, 1H), 0.94 (s, 3H).

[0098] II. Catalytic Reaction Experiment

[0099] This example uses 17 synthesized chiral iridium complexes as catalysts for asymmetric reductive amination and asymmetric hydrogen transfer reductive amination reactions to synthesize chiral primary amines. Details are as follows:

[0100] The technical route for asymmetric reductive amination is as follows:

[0101]

[0102] The asymmetric reductive amination reaction specifically involved the following steps: In a glove box, the substrate (0.2 mmol), NH4OAc (46.2 mg, 0.6 mmol, 3 equiv.), catalyst (1.0 μmol, 0.5 mol%), and AgOTf (1.3 mg, 5.0 μmol, 5 mol%, if applicable) were sequentially added to a 2 mL long-necked ampoule. A suitable magnetic stir bar was placed inside. Finally, solvent (1.0 mL) and acetic acid (24.0 mg, 0.4 mmol, 2 equiv.) were added. The ampoule was transferred to an autoclave, which was then removed from the glove box. 30 bar of H2 was introduced into the autoclave, and the mixture was stirred at 80 °C for 20 h. After the reaction was complete, the mixture was cooled to room temperature, and the residual pressure in the autoclave was slowly released. 1,3,5-trimethoxybenzene (0.1 mmol, 16.8 mg) was added to the reaction system and stirred thoroughly until completely dissolved. Take 0.1 mL of the above solution and dilute it to 0.5 mL with MeOH-d4. 1 The conversion and yield of the reaction were determined by quantitative nuclear magnetic resonance (NMR) at 1H NMR. The remaining reaction solution was rotary evaporated to dryness, and 1.0 M hydrochloric acid (3.0 mL) was added to the residue. Extraction was performed with ethyl acetate (3 mL × 3). The aqueous phase was adjusted to pH 8 with NaHCO3, followed by extraction with dichloromethane (5 mL × 3). The dichloromethane phases were combined, dried over anhydrous sodium sulfate, filtered, and rotary evaporated to obtain the chiral amine compound. The obtained chiral amine compound was dissolved in dichloromethane (1.0 mL), and acetic anhydride or benzoyl chloride (1.5 equivalents) and triethylamine (2.0 equivalents) were added. The mixture was stirred at room temperature for 0.5 hours. The obtained amine-protected chiral amide compounds were purified by thin-layer chromatography, and their ee values ​​were determined by chiral HPLC.

[0103] The catalyst is the chiral iridium complex prepared in this example. AgOTf is only required when K7 is used as the substrate and complex 1, complex 2, complex 3, complex 4, complex 5, complex 6, complex 10 or complex 15 is used as the catalyst.

[0104] The technical route for the asymmetric hydrogen transfer reductive amination reaction is as follows:

[0105]

[0106] The asymmetric hydrogen transfer reductive amination reaction specifically includes: under an argon atmosphere, adding substrate (0.2 mmol), HCOONH4 (37.8 mg, 0.6 mmol, 3 equiv), iridium catalyst (0.5–1.0 μmol, 0.25–0.5 mol%), and hydrogen source (0.4–0.6 mmol) to a Schlenk tube connected to a double-row tube, followed by the addition of solvent (1.0 mL). The reaction is stirred at 80 °C for 16 h. After the reaction is complete, the mixture is cooled to room temperature, and 1,3,5-trimethoxybenzene (0.1 mmol, 16.8 mg) is added to the reaction system and stirred thoroughly until completely dissolved. 0.1 mL of the solution is then diluted to 0.5 mL with MeOH-d4. 1 The conversion and yield of the reaction were determined by quantitative nuclear magnetic resonance (NMR) at 1H NMR. The remaining reaction solution was rotary evaporated to dryness, and 1.0 M hydrochloric acid (3.0 mL) was added to the residue. The residue was extracted with ethyl acetate (3 mL × 3). The aqueous phase was adjusted to pH 8 with NaHCO3 and then extracted with dichloromethane (5 mL × 3). The dichloromethane phases were combined, dried over anhydrous sodium sulfate, filtered, and rotary evaporated to obtain the chiral amine compound. The obtained chiral amine compound was dissolved in dichloromethane (1.0 mL), and acetic anhydride or benzoyl chloride (1.5 equivalents) and triethylamine (2.0 equivalents) were added. The mixture was stirred at room temperature for 0.5 hours. The obtained amine-protected chiral amide compounds were purified by thin-layer chromatography and their ee values ​​were determined by chiral HPLC. The iridium catalyst used was the chiral iridium complex prepared in this example.

[0107] It should be noted that for substrate K7, due to the sterically hindered adamantyl group, the amine in the product 1-adamantyl-phenylmethylamine is difficult to protonate, or the protonated product is soluble in ethyl acetate. Therefore, the above post-treatment method can only separate trace amounts of the product, although the actual reaction yield is relatively high. The improved post-treatment method is as follows: 1 After determining the conversion and yield of the reaction by ¹H NMR, the remaining reaction solution was poured into water (2 mL), alkalized with sodium carbonate to pH = 10, and then extracted with dichloromethane (3 mL × 3). The dichloromethane phases were combined, dried with anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the chiral 1-adamantyl-phenylmethylamine compound. The obtained chiral 1-adamantyl-phenylmethylamine compound was dissolved in dichloromethane (1.0 mL), and benzoyl chloride (1.5 equivalents) and triethylamine (2.0 equivalents) were added. The mixture was stirred at room temperature for 0.5 hours. The obtained benzoyl-protected amino chiral compound was purified by preparative thin-layer chromatography, and its ee value was determined by chiral HPLC. Chiral HPLC method: Chiralpak IB column, n-hexane / isopropanol = 95 / 5; flow rate = 1 mL / min, separation time 30 min; detection at 220 nm. Retention time: t1 = 11.35 min, t2 = 20.58 min.

[0108] The 15 substrate ketones used in this example, namely K1 to K15, are as follows:

[0109]

[0110] Table 1 shows some data for the asymmetric reductive amination reaction catalyzed by the chiral iridium complex in this example.

[0111] Table 1. Products of asymmetric reductive amination catalyzed by chiral iridium complexes.

[0112]

[0113]

[0114] The results of the asymmetric reductive amination reaction catalyzed by the chiral iridium complex in this example for the synthesis of chiral primary amines show that the characteristics of the asymmetric reductive amination reaction of ketones catalyzed by the chiral CpIr(III) complex prepared in this example can be summarized as follows: ① The complex has high reductive amination activity for various types of ketones. At a catalyst loading of 0.5 mol%, the yield of some chiral primary amines can reach up to 99%, although for some cyclic ketone substrates such as 1-indanone, 1-tetrahydronaphthone, and the sterically hindered 1-naphthylethylone, the yield of the corresponding chiral primary amine can only reach 60%-70%. However, this is still much higher than the catalytic activity of the bisphosphine-Ru(OAc)2 system; ② For substrates with similar steric hindrance, the asymmetric reductive amination reaction catalyzed by chiral CpIr(III) complexes gives similar enantioselectivity, such as the ee value of 1-phenylethylamine, 1-indeneamine, and 1-tetrahydronaphthylamine, etc., when using complex 16 as a catalyst; ③ Chiral CpIr(III) complexes give better diastereoselectivity for substrates with large overall steric hindrance without affecting their reactivity. For example, considering the catalytic data of complex 16, compared to the 35% ee value of 1-phenylethylamine, the ee values ​​of sterically hindered phenyl-cyclohexylmethylamine, phenyl-tert-butylmethylamine, phenyl-tert-pentylmethylamine, and phenyl-1-adamantylmethylamine are 61%, 50%, 56%, and 65%, respectively; ④ Catalytic reactions require a certain degree of steric hindrance on both sides of the ketone carbonyl group. As long as one side has a small steric hindrance, even if the other side has a large steric hindrance, the asymmetric control is still very poor. For example, the ee values ​​of 1-adamantyl ethyl ketone, tert-butyl ethyl ketone, and cyclohexyl ethyl ketone for generating the corresponding chiral primary amines are only -4%, -22%, and -12%, respectively; ⑤ The catalytic effect of chiral CpIr(III) complexes based on pyridine carboxamide auxiliary ligands is similar to that of iridium complexes based on imine auxiliary ligands. Currently, the highest ee value that can be achieved is 65%, with a catalyst loading of 0.5 mol%, and its dosage can be further reduced. The catalytic activity and substrate applicability are better than the bisphosphine-Ru(OAc)2 system. More importantly, the above experimental results reveal the structure-activity relationship between the catalyst's structure and its catalytic activity and enantioselectivity, as well as the matching relationship between the catalyst structure and the substrate, laying the foundation for designing more efficient and practical catalysts.

[0115] In this example, the ee value means enantiomeric excess, representing the percentage of a mixture of enantiomers where one isomer (R) is present in greater quantity than another isomer (S). A positive ee value indicates that R is more abundant than S, and a negative ee value indicates that S is more abundant than R. The absolute value of the ee value is more indicative of the desired product; if an opposite configuration product is desired, a catalyst with the opposite configuration can be used.

[0116] Table 2 shows some data for the asymmetric hydrogen transfer reductive amination reaction catalyzed by the chiral iridium complex in this example.

[0117] Table 2. Products of asymmetric hydrogen transfer reductive amination catalyzed by chiral iridium complexes.

[0118]

[0119]

[0120] The results of the asymmetric hydrogen transfer reduction amination reaction catalyzed by the chiral iridium complex to synthesize chiral primary amines show that increasing the steric hindrance of the catalyst at appropriate positions in the complex can effectively improve the enantioselectivity of the catalyst. However, when the introduced steric hindrance is too large (such as tert-butyl), the configuration of the product will be reversed, and the introduction of steric hindrance at the ortho position of the ligand amine will lead to a simultaneous decrease in the activity and enantioselectivity of the catalytic reaction.

[0121] For the representative and well-catalyzed complexes 3, 4, and 10, this example also tested their asymmetric hydrogen transfer reduction amination catalysis using formic acid as the hydrogen source, and compared them with Cramer-type binaphthalene CpIr-nitrogen-carbon bidentate complexes 15 and 16. The experimental results show that Cramer's chiral binaphthalene CpIr-nitrogen-carbon bidentate complexes have poor activity and enantioselectivity when used as hydrogen transfer reduction amination catalysts. Conversely, the chiral binaphthalene CpIr-pyridinecarboxamide bidentate complex designed and synthesized in this example can be used for both asymmetric reduction amination and asymmetric hydrogen transfer reduction amination reactions, and the latter system generally yields better results than the former. Currently, complex 10 shows the best catalytic performance, achieving an ee value of 70% and a yield of 84% using formic acid as the hydrogen source.

[0122] When the meta-substituent of the ligand amine is dimethyl (complex 3) and di-tert-butyl (complex 4), the resulting products have different configurations, indicating that the product structure has inverted. Based on the experimental data from both asymmetric reductive amination and asymmetric hydrogen transfer reductive amination reactions, it is believed that a appropriately sized group exists at the meta-position of the ligand amine to prevent configuration inversion. Therefore, it is necessary to further optimize the catalyst structure by introducing a sterically hindered group between methyl and tert-butyl at the meta-position of the ligand amine. This would both utilize the steric hindrance effect to improve the enantioselectivity of the reaction and reasonably control the steric hindrance to ensure that the product configuration does not invert. To this end, complexes 7 to 9 were designed and synthesized, and their activity and enantioselectivity in catalyzing asymmetric hydrogen transfer reductive amination were tested. Although their reactivity was excellent, with yields easily exceeding 90% at a catalyst loading of 0.5 mol%, their enantioselectivity actually decreased. Considering that ethoxy, methoxy, and ethyl groups have stronger electron-donating properties than methyl groups, but their corresponding complexes exhibit worse enantioselectivity, it was hypothesized that complexes containing electron-withdrawing groups might achieve better enantioselectivity. Therefore, this example synthesized a ligand with a bis(trifluoromethyl) group at the meta-position of the amine and its corresponding complex 11, and tested its catalytic performance. However, complex 11 showed poor enantioselectivity for the asymmetric hydrogen transfer reductive amination reaction, with an ee value of only -20%, although its catalytic activity remained excellent. Currently, the best-performing catalyst is complex 10, which achieves an 84% yield and an ee value of 70% for the asymmetric hydrogen transfer reductive amination of phenyl-1-adamantyl methyl ketone under formic acid as the hydrogen source.

[0123] All the complexes prepared in this example, complex 1, complex 1a, and complexes 2 to 16, were obtained by column chromatography in air. For example, the single crystal of complex 1a was grown in air. Therefore, it can be considered that the chiral iridium complexes prepared in this example have good air stability and can be stored in air.

[0124] Furthermore, in this example, the deuterated chloroform solution of complex 1 was placed in an NMR tube and left in air at room temperature for one week. During this period, the solvent was completely evaporated, and deuterated chloroform was added back in. After one week, complex 1 was analyzed by 1H NMR spectroscopy, with freshly prepared complex 1 used as a control. The results showed that the 1H NMR characterization data did not change significantly, indicating that complex 1 can be stored in air for a long time.

[0125] The above description, in conjunction with specific embodiments, provides a further detailed explanation of this application and should not be construed as limiting the specific implementation of this application to these descriptions. Those skilled in the art to which this application pertains can make several simple deductions or substitutions without departing from the concept of this application.

Claims

1. A chiral iridium complex, characterized in that: The chiral iridium complex is at least one of complex 1, complex 1a, complex 2 to complex 4, complex 7 to complex 11, and complex 13 to complex 16; 。 2. A method for preparing chiral primary amines using an asymmetric reductive amination reaction, characterized in that: This includes catalytic reactions using ketones as substrates in solvents with amine and hydrogen sources, as follows: ， Wherein, the catalyst is the chiral iridium complex according to claim 1, R7 is phenyl, and R8 is selected from methyl, cyclohexyl, tert-butyl, tert-amyl, and adamantyl. The hydrogen source is hydrogen gas; The solvent is 1,1,1,3,3,3-hexafluoroisopropanol.

3. The method according to claim 2, characterized in that: The amine source is at least one of ammonium formate, ammonium acetate, ammonium salicylate, ammonium fluoride, ammonium chloride, ammonium sulfate, and ammonia.

4. The method according to claim 2, characterized in that: The reaction system also contains an additive, namely AgOTf.

5. A method for preparing chiral primary amines using an asymmetric hydrogen transfer reducing amination reaction, characterized in that: This includes catalytic reactions using ketones as substrates in solvents with amine and hydrogen sources, as follows: ， Wherein, the catalyst is complex 1, complex 1a, complex 2 to complex 4, complex 7 to complex 10 of the chiral iridium complex according to claim 1, R7 is selected from phenyl, and R8 is selected from methyl, ester group, carboxylic acid group, cyclohexyl, tert-butyl, tert-amyl, adamantyl; The hydrogen source is formic acid; The solvent is 1,1,1,3,3,3-hexafluoroisopropanol.

6. The method according to claim 5, characterized in that: The amine source is at least one of ammonium formate, ammonium acetate, ammonium salicylate, ammonium fluoride, ammonium chloride, ammonium sulfate, and ammonia.

7. The method according to claim 5, characterized in that: The reaction system also contains an additive, namely AgOTf.

8. The method for preparing the chiral iridium complex according to claim 1, characterized in that: The chiral iridium complex is prepared using at least one of the following methods; Method 1 includes the use of chiral iridium dimer compounds [Ir (OMe) The chiral iridium complex was prepared by heating Cp*I2]2, amide ligands and K2CO3 in p-xylene under reflux. Method 2 includes the use of chiral iridium dimer compounds [Ir (OMe) The chiral iridium complex was prepared by heating and refluxing Cp*I2]2, imine ligand and sodium acetate in 1,2-dichloroethane; The chiral iridium dimer compound [Ir (OMe) The structural formula of Cp*I2]2 is as follows. 。 9. The preparation method according to claim 8, characterized in that: The heating reflux temperature is 80-140 ℃, and the reaction time is 20-28 h.

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