Buchwald-Hartwig Amination Reaction Research Articles

Palladium Complexes Derived from Waste as Catalysts for C-H Functionalisation and C-N Bond Formation

Three-way catalysts (TWCs) are widely used in vehicles to convert the exhaust emissions from internal combustion engines into less toxic pollutants. After around 8–10 years of use, the declining catalytic activity of TWCs causes them to need replacing, leading to the generation of substantial amounts of spent TWC material containing precious metals, including palladium. It has previously been reported that [NnBu4]2[Pd2I6] is obtained in high yield and purity from model TWC material using a simple, inexpensive and mild reaction based on tetrabutylammonium iodide in the presence of iodine. In this contribution, it is shown that, through a simple ligand exchange reaction, this dimeric recovery complex can be converted into PdI2(dppf) (dppf = 1,1′-bis(diphenylphosphino)ferrocene), which is a direct analogue of a commonly used catalyst, PdCl2(dppf). [NnBu4]2[Pd2I6] displayed high catalytic activity in the oxidative functionalisation of benzo[h]quinoline to 10-alkoxybenzo[h]quinoline and 8-methylquinoline to 8-(methoxymethyl)quinoline in the presence of an oxidant, PhI(OAc)2. Near-quantitative conversions to the desired product were obtained using a catalyst recovered from waste under milder conditions (50 °C, 1–2 mol% Pd loading) and shorter reaction times (2 h) than those typically used in the literature. The [NnBu4]2[Pd2I6] catalyst could also be recovered and re-used multiple times after the reaction, providing additional sustainability benefits. Both [NnBu4]2[Pd2I6] and PdI2(dppf) were also found to be active in Buchwald–Hartwig amination reactions, and their performance was optimised through a Design of Experiments (DoE) study. The optimised conditions for this waste-derived palladium catalyst (1–2 mol% Pd loading, 3–6 mol% of dppf) in a bioderived solvent, cyclopentyl methyl ether (CPME), offer a more sustainable approach to C-N bond formation than comparable amination protocols.

Palladium-catalyzed C-N Coupling Reactions in the Synthesis of Dibenzodiazepines

Abstract: In today’s world, aryl halides have attracted our attention toward the amination reactions catalyzed by palladium. In this review article, there are some selected developments in the field of catalysis, and the Buchwald-Hartwig amination reaction is one of them. It is a common and highly efficient method reported for forming dibenzodiazepines. The readily accessible precursors and ammonia undergo cross-coupling reactions in the presence of a palladium catalyst; after that, the intermediate immediately undergoes intramolecular condensation to give the desired dibenzodiazepines in one step. Due to the structural characteristics of these compounds, the potential for diversification - principally for functional group incorporation - is immense. New and advanced technologies are also employed to form these medicinally important molecules and are reviewed here. Our purpose is to inform the researchers about recent advances in this protocol for the C-N bond formation, especially used for synthesizing dibenzodiazepines.

Syntheses and Electrochemical and EPR Studies of Porphyrins Functionalized with Bulky Aromatic Amine Donors.

A series of nickel(II) porphyrins bearing one or two bulky nitrogen donors at the meso positions were prepared by using Ullmann methodology or more classical Buchwald-Hartwig amination reactions to create the new C-N bonds. For several new compounds, single crystals were obtained, and the X-ray structures were solved. The electrochemical data of these compounds are reported. For a few representative examples, spectroelectrochemical measurements were used to clarify the electron exchange process. In addition, a detailed electron paramagnetic resonance (EPR) study was performed to estimate the extent of delocalization of the generated radical cations. In particular, electron nuclear double resonance spectroscopy (ENDOR) was used to determine the coupling constants. DFT calculations were conducted to corroborate the EPR spectroscopic data.

Recent Achievements in the Copper-Catalyzed Arylation of Adamantane-Containing Amines, Di- and Polyamines

Rapid development of the copper-catalyzed amination of aryl halides in the beginning of the 21st century, known as the Renaissance of the Ullmann chemistry, laid foundations for the use of this method as a powerful tool for the construction of the C(sp2)-N bond and became a rival of the Buchwald–Hartwig amination reaction. Various applications of this approach are well-documented in a number of comprehensive and more specialized reviews, and this overview in the form of a personal account of the Cu-catalyzed arylation and heteroarylation of the adamantane-containing amines, and di- and polyamines, covers a more specific area, showing the possibilities of the method and outlining general regularities, considering reagents structure, copper source and ligands, scope, and limitations. The material of the last decade is mainly considered, and recent data on the application of the unsupported copper nanoparticles and possibilities of the Chan-Lam reaction as an alternative to the use of aryl halides are also discussed.

Digitizing chemical discovery with a Bayesian explorer for interpreting reactivity data

Interpreting the outcome of chemistry experiments consistently is slow and frequently introduces unwanted hidden bias. This difficulty limits the scale of collectable data and often leads to exclusion of negative results, which severely limits progress in the field. What is needed is a way to standardize the discovery process and accelerate the interpretation of high-dimensional data aided by the expert chemist's intuition. We demonstrate a digital Oracle that interprets chemical reactivity using probability. By carrying out >500 reactions covering a large space and retaining both the positive and negative results, the Oracle was able to rediscover eight historically important reactions including the aldol condensation, Buchwald-Hartwig amination, Heck, Mannich, Sonogashira, Suzuki, Wittig, and Wittig-Horner reactions. This paradigm for decoding reactivity validates and formalizes the expert chemist's experience and intuition, providing a quantitative criterion of discovery scalable to all available experimental data.

The Asymmetric Buchwald–Hartwig Amination Reaction

AbstractOver the past few decades, the Buchwald–Hartwig reaction has emerged as a powerful tool for forging C−N bonds, and has been vital to the pharmaceuticals, materials, and catalysis fields. However, asymmetric Buchwald–Hartwig amination reactions for constructing centered chirality, planar chirality, and axial chirality remain in their infancy owing to limited substrate scope and laggard ligand design. The recent surge in interest in the synthesis of C−N/N−N atropisomers, has witnessed a renaissance in asymmetric Buchwald–Hartwig amination chemistry as the first practical protocol for the preparation of C−N atropisomers. This review highlights reported asymmetric Buchwald–Hartwig amination protocols and provides a brief overview of their chemical practicality.

The Asymmetric Buchwald-Hartwig Amination Reaction.

Over the past few decades, the Buchwald-Hartwig reaction has emerged as a powerful tool for forging C-N bonds, and has been vital to the pharmaceuticals, materials, and catalysis fields. However, asymmetric Buchwald-Hartwig amination reactions for constructing centered chirality, planar chirality, and axial chirality remain in their infancy owing to limited substrate scope and laggard ligand design. The recent surge in interest in the synthesis of C-N/N-N atropisomers, has witnessed a renaissance in asymmetric Buchwald-Hartwig amination chemistry as the first practical protocol for the preparation of C-N atropisomers. This review highlights reported asymmetric Buchwald-Hartwig amination protocols and provides a brief overview of their chemical practicality.

N-Indole-substituted N-heterocyclic carbene palladium precatalysts: Synthesis, characterization and catalytic cross-couplings

PEPPSI-type Pd complexes featuring NHC ligands with N-(4-indolyl) side chains were synthesized, characterized, and evaluated in Suzuki-Miyaura cross-coupling, Buchwald-Hartwig amination and Heck reaction. Complex 8g, containing an unsymmetric N-(3-isopropyl-1,5,7-trimethyl-2-phenylindol-4-yl) NHC, was found the most active in the series and outperformed Pd-PEPPSI-IPr. The results demonstrated that N-(4-indolyl) side chain is a promising platform for developing synthetically useful NHC ligands.

Dicyanopyrazino phenanthrene based charge transfer derivatives: Role of amine donor in tuning of photophysical, aggregation-induced emission, electrochemical and theoretical properties

Herein Buchwald-Hartwig amination reaction employed for the synthesis of donor−acceptor−donor (D−A−D) structured, C–N coupled 2,3−dicyanopyrazino phenanthrene (DCPP) amines 2‒6. Further dyes characterized by spectroscopic viz. NMR, MALDI-TOF, IR techniques. The acquired intramolecular charge transfer (ICT) (λICT = 403–490 nm) transitions by donation of electron from donor to acceptor via C–N coupling in dyes confer D−A assembly. Also ICT properties of dyes found aligned with the donating strength of coupled amine in dyes. As a result dyes emit in blue−green region (λemi = 469–549 nm) in solution and solid film along with notable positive solvatochromism. Moreover aggregation-induced emission (AIE) characteristics in dyes found affected by the size of nanoparticle formed in THF/H2O media. Accordingly dye 2 and 6 exhibit AIE property among other dyes due to formation of emissive, small size nanoparticles in the media. Further comparable HOMO (−5.19 to −5.83 eV) and LUMO (−3.02 to −3.27 eV) energies of dyes with reported small organic ambipolar materials are remarkable towards its utilization in organic electronics. The band gap (2.16 to 2.66 eV) are also matches well with reported blue-emitting organic semiconductors. Density functional theory (DFT) and time-dependent density-functional theory (TDDFT) calculations agree with the experimental opto-electrochemical data. Thus opto-electrochemical properties possess by dyes undersigned its desired application in optoelectronic devices.

A convenient synthesis of linezolid through Buchwald-Hartwig amination

A new method was developed for the synthesis of Linezolid from commercially available (R)-3-(4-bromo-3-fluorophenyl)-5-(hydroxymethyl)oxazolidin-2-one. Linezolid is an antibiotic belongs to the family of oxazolidinones, it is successfully synthesized through a new method which include Buchwald-Hartwig amination reaction and Gabriel amine synthesis as the key steps. The synthetic route is easy to perform and with high yield. This new method provides a huge possibility for the synthesis of new linezolid derivatives that may possibly tackle the problem of bacteria resistance to oxazolidinones.

Bis(imino)acenaphthene N‐Heterocyclic Carbene Palladium Complexes Bearing Tertiary Amines: Structural and Catalytic Studies on the Interaction between Soft Acid and Hard Base

AbstractThe HSAB principle in designing Bis(imino)acenaphthene N‐heterocyclic carbene (NHC) palladium complexes is presented. N‐donor ligands serve as hard bases to enhance the catalytic activities of NHC Pd complexes in Suzuki and Buchwald–Hartwig amination reactions. The Pd complex bearing tertiary amine ligands exhibited higher performance in coupling reactions than those exhibited by other soft base ligands reported in literature. 48 coupling products were generated in moderate‐to‐complete yields in the presence of aryl chlorides as substrates for Suzuki and amination reactions in air under mild conditions.

Enhancing the Intermolecular Interactions of Ladder-Type Heteroheptacene-Based Nonfullerene Acceptors for Efficient Polymer Solar Cells by Incorporating Asymmetric Side Chains

Enhancing the Intermolecular Interactions of Ladder-Type Heteroheptacene-Based Nonfullerene Acceptors for Efficient Polymer Solar Cells by Incorporating Asymmetric Side Chains

Recent Applications of Pd-Catalyzed Suzuki–Miyaura and Buchwald–Hartwig Couplings in Pharmaceutical Process Chemistry

Cross-coupling reactions have changed the way complex molecules are synthesized. In particular, Suzuki–Miyaura and Buchwald–Hartwig amination reactions have given opportunities to elegantly make pharmaceutical ingredients. Indeed, these reactions are at the forefront of both the stages of drug development, medicinal chemistry, and process chemistry. On the one hand, these reactions have given medicinal chemists a resource to derivatize the core compound to arrive at scaffold rapidly. On the other hand, these cross couplings have offered the process chemists a smart tool to synthesize the development candidates safely, quickly, and efficiently. Generally, the application of cross-coupling reactions is broad. This review will specifically focus on their real (pharma) world applications in large-scale synthesis appearing in the last three years.

XGBoost-based intelligence yield prediction and reaction factors analysis of amination reaction.

Buchwald-Hartwig amination reaction catalyzed by palladium plays an important role in drug synthesis. In the last few years, machine learning-assisted strategies emerged and quickly gained attention. In this article, an importance and relevance-based integrated feature screening method is proposed to effectively filter high-dimensional feature descriptor data. Then, a regularized machine learning boosting tree model, eXtreme Gradient Boosting, is introduced to intelligently predict reaction performance in multidimensional chemistry space. Furthermore, convergence, interpretability, generalization, and the internal association between reaction conditions and yields are excavated, which provides intelligent assistance for the optimal design of coupling reaction system and evaluating the reaction conditions. Compared with recently published results, the proposed method requires fewer feature descriptors, takes less time, and achieves more accurate prediction accuracy.

D−A−D based pyrido-pyrazino[2,3-b]indole amines as blue-red fluorescent dyes: Photophysical, aggregation-induced emission, electrochemical and theoretical studies

Herein donor−acceptor−donor (D−A−D) structured, pyridopyrazino[2,3-b]indole amines 2–6 were designed and synthesized via C–N coupled Buchwald-Hartwig amination reaction and characterized by spectroscopic methods. C–N coupling in molecules offers intramolecular charge transfer (ICT) transitions at longer wavelengths (λmax = 400–459 nm) in absorption spectra reminiscent D−A assembly. Dyes covers broad range of emission and emit in blue to red region with emission maxima 433–600 nm in solvent and solid film. Dyes 2, 5 and 6 explore the aggregation-induced emission (AIE) characteristics. Further C–N blending of various donor with pyridopyrazino[2,3-b]indole acceptor results in suppressed band gap (1.99–2.43 eV) and comparable HOMO (−5.17 to −5.71 eV) and LUMO (−3.18 to −3.28 eV) energies with reported small organic ambipolar materials. DFT and TDDFT calculations agree with the experimental opto-electrochemical data. Moreover, computed small singlet and triplet excitation energy difference (ΔEST (0.01–0.14 eV)) suggest thermally activated delayed fluorescent (TADF) emitting properties of dyes. Thus pyridopyrazino[2,3−b]indole amine dyes propose their potential application in optoelectronic devices.

Kernel Methods for Predicting Yields of Chemical Reactions.

The use of machine learning methods for the prediction of reaction yield is an emerging area. We demonstrate the applicability of support vector regression (SVR) for predicting reaction yields, using combinatorial data. Molecular descriptors used in regression tasks related to chemical reactivity have often been based on time-consuming, computationally demanding quantum chemical calculations, usually density functional theory. Structure-based descriptors (molecular fingerprints and molecular graphs) are quicker and easier to calculate and are applicable to any molecule. In this study, SVR models built on structure-based descriptors were compared to models built on quantum chemical descriptors. The models were evaluated along the dimension of each reaction component in a set of Buchwald-Hartwig amination reactions. The structure-based SVR models outperformed the quantum chemical SVR models, along the dimension of each reaction component. The applicability of the models was assessed with respect to similarity to training. Prospective predictions of unseen Buchwald-Hartwig reactions are presented for synthetic assessment, to validate the generalizability of the models, with particular interest along the aryl halide dimension.

Cross-Coupling Reactions of Nitroarenes

Cross-coupling reactions are powerful synthetic tools to construct diverse chemical bonds often found in, for example, advanced materials and pharmaceuticals. Since their discovery, haloarenes have habitually been used as electrophilic coupling partners both in academic and industrial contexts. However, concerning the efficiency and the often-negative environmental impact of haloarene-based cross-coupling processes, more readily available, inexpensive, and environmentally friendly electrophiles have been explored.Nitroarenes, for example, are obtained from the facile nitration of aromatic compounds and, thus, represent one of the most easy-to-access feedstock electrophiles. Furthermore, their electron-deficient arene core can be functionalized easily and site-selectively through a wide variety of reactions. Yet, despite these advantages and even though the direct transformation of the NO2 group would be an attractive option in cross-coupling chemistry, it has so far remained difficult to convert nitroarenes via a cleavage of the Ar-NO2 bond given the inherent reactivity (or the lack thereof) of the nitro group. Such denitrative conversion has been performed by a conventional sequence of reduction, diazotization, and Sandmeyer reactions, which severely lacks efficiency and generality.This Account summarizes our recent research progress on cross-coupling reactions that employ nitroarenes as electrophiles. First, we developed the Suzuki-Miyaura coupling of nitroarenes using a palladium/BrettPhos catalyst. This reaction proceeds via an (at the time) unprecedented oxidative addition of the Ar-NO2 bond, which was supported by experimental results and theoretical calculations. A widely accepted catalytic cycle for Pd-catalyzed cross-couplings has since been extended to include nitroarenes as electrophiles, which significantly increases substrate generality. Second, this denitrative coupling protocol was applied to various bond-forming reactions, namely, Buchwald-Hartwig amination, etherification, and hydrogenation reactions. Such diversification has enhanced the utility of nitroarenes as cross-coupling partners. To develop each reaction, it was necessary to modify the reaction conditions as required to overcome the obstacles deriving from nitro functionality including transmetalation and side reactions, as well as oxidative addition. Third, we designed a new Pd/NHC catalyst that exhibits higher activity than Pd/BrettPhos. The improved performance of Pd/NHC system was supported by its strong electron-donicity and structural robustness, and it allows the reduction of the catalyst loading significantly, thus increasing the efficacy and practicality of this method.The field of nitroarene-based cross-coupling has just started to flourish. In addition to our original work, several research groups have already adopted Pd/BrettPhos or Pd/NHC catalysts to develop new denitrative functionalizations. The utility of nitroarenes in the context of organic synthesis should be now revisited.

Total Synthesis of Chalaniline B: An Antibiotic Aminoxanthone from Vorinostat-Treated Fungus Chalara sp. 6661.

Chalaniline B [1-anilino-2,8-dihydroxy-3-(hydroxymethyl)xanthone], an antibiotic previously isolated from vorinostat-treated Chalara sp., was prepared in 7 steps from 2-hydroxyxanthone by a route incorporating regioselective oxidative transformations (bromination at C1/C3, ketone directed Pd(II)-catalyzed hydroxylation at C8), installation of the C1-anilino moiety by a regioselective Buchwald-Hartwig amination reaction from 1,3-dibromo-2,8-dimethoxyxanthone, and late-stage hydroxymethylation at C3 using a Stille cross-coupling. Biological evaluation of deshydroxymethylchalaniline B (1-anilino-2,8-dihydroxyxanthone) revealed MIC values of 8 μg mL-1 (25 μM) against both methicillin resistant S. aureus and B. subtilis.

Intelligent predicting reaction performance in multi-dimensional chemical space using quantile regression forest

Buchwald-Hartwig amination reaction is widely applied in synthetic organic chemistry, which faces tedious and complex experimental process. In 2018, an interesting yield prediction technique is proposed via machine learning (random forest) in Science. However, the method is based on point prediction with many feature descriptors. For tackling these problems, complements and improvements have been made from the perspectives of machine learning and statistics, including feature dimensionality reduction, distributed prediction and visualization, so as to provide accurate and reliable decision information.

Controlling Regioselectivity in Palladium-Catalyzed C-H Activation/Aryl-Aryl Coupling of 4-Phenylamino[2.2]paracyclophane.

Selective activation/functionalization of C−H bonds has emerged as an atom‐ and step‐economical process at the forefront of modern synthetic chemistry. This work reports palladium‐catalyzed exclusively para‐selective C−H activation/aryl–aryl bond formation with a preference over N‐arylation under the Buchwald–Hartwig amination reaction of 4‐phenylamino[2.2]paracyclophane. This innovative synthetic strategy allows a facile preparation of [2.2]paracyclophane derivatives featuring disparate para‐substitutions at C‐4 and C‐7 positions in a highly selective manner, gives access to a series of potential candidates for [2.2]paracyclophane‐derived new planar chiral ligands. The unprecedented behavior in reactivity and preferential selectivity of C−C coupling over C−N bond formation via C−H activation is unique to the [2.2]paracyclophane scaffold compared to the non‐cyclophane analogue under the same reaction conditions. Selective C−H activation/aryl–aryl bond formation and sequential C−N coupling product formation is evidenced unambiguously by X‐ray crystallography.