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The functionalization of unactivated carbon–hydrogen (C–H) bonds is a transformative strategy for the rapid construction of molecular complexity given the ubiquitous presence of C–H bonds in organic molecules. It represents a powerful tool for accelerating the synthesis of natural products and bioactive compounds while reducing the environmental and economic costs of synthesis. At the same time, the ubiquity and strength of C–H bonds also present major challenges towards the realization of transformations which are both highly selective and efficient. The development of practical C–H functionalization reactions has thus remained a compelling yet elusive goal in organic chemistry for over a century.
Specifically, the capability to form useful new C–C, C–N, C–O, and C–X bonds via direct C–H functionalization would have wide-ranging impacts in organic synthesis. Palladium (Pd) is especially attractive as a catalyst for such C–H functionalizations owing to the diverse reactivity of intermediate palladium–carbon bonds. Early efforts using cyclopalladation with Pd(OAc)2 and related salts led to the development of many Pd-catalyzed C–H functionalization reactions. However, Pd(OAc)2 and other simple Pd salts only perform racemic transformations, which prompted a long search for effective chiral catalysts dating back to the 1970s. Pd salts also have low reactivity with synthetically useful substrates. To address these issues, effective and reliable ligands capable of accelerating and improving the selectivity of Pd-catalyzed C–H functionalizations are needed.
In this Account, we highlight the discovery and development of bifunctional mono-N-protected amino acid (MPAA) ligands, which make great strides towards addressing these two challenges. MPAAs enable numerous Pd(II)-catalyzed C(sp2)–H and C(sp3)–H functionalization reactions of synthetically relevant substrates under operationally practical conditions and with excellent stereoselectivity when applicable. Mechanistic studies indicate that MPAAs operate as a unique bifunctional ligand for C–H activation in which both the carboxylate and amide are coordinated to Pd. The N-acyl group plays an active role in the C–H cleavage step, greatly accelerating C–H activation. The rigid MPAA chelation also results in a predictable transfer of chiral information from a single chiral center on the ligand to the substrate and permits the development of a rational stereomodel to predict the stereochemical outcome of enantioselective reactions.
We also describe the application of MPAA-enabled C–H functionalization in total synthesis and provide an outlook for future development in this area. We anticipate that MPAAs and related next generation ligands will continue to stimulate development in the field of Pd-catalyzed C–H functionalization.
While transition metal-catalyzed carbon–hydrogen (C–H) bond functionalization has received a great deal of attention during the past few decades,1 developing effective strategies to transform the C–H bonds of complex substrates into useful functional groups (such as hydroxyl, amino, halide, and aryl or alkyl groups) remains a great challenge in catalysis.1f Palladium (Pd), among many transition metals, has proven to be versatile in C–H functionalization.2 However, core challenges remain, namely the activation of C–H bonds of synthetically useful substrates (i.e. the use of native functional groups or common protecting groups as directing groups), achieving high site selectivity, and most important, achieving enantioselectivity. Effective ligands capable of accelerating C–H cleavage3 and improving the selectivity of Pd-catalyzed C–H functionalization reactions could greatly facilitate the achievement of the aforementioned objectives.4
Ligands can play a major role in C–H functionalizations by modulating both the C–H bond cleavage (C–H activation) and C–C/C–heteroatom bond formation steps. Their coordination with palladium can change the reactivity and structure of the metal, and consequently lower the activation energy of elementary steps. By energetically favoring the pathways that lead to a desired product, ligands can improve the Pd catalyst’s site selectivity and stereoselectivity.5 Ligands also can improve the solubility of palladium catalysts in organic solvents and stabilize the catalyst, increasing the concentration of the active species throughout the reaction.
Mono-N-protected amino acids (MPAAs) as bidentate ligands for Pd-catalyzed C–H functionalizations were first introduced by our laboratory in 2008 ( ).6 Mechanistic studies (vide infra) have indicated that the MPAA ligands bind to Pd(II) in a bidentate manner and actively participate in C–H cleavage,7 in contrast to most known ligands, which modulate a metal’s properties but do not participate in catalytic steps. One notable exception is the diamine ligand in Noyori’s asymmetric transfer hydrogenation, in which the ligand nitrogen both heterolytically cleaves H2 and transfers a hydrogen atom to the carbonyl oxygen.8 Milstein has also reported metal-ligand cooperation with pincer complexes.9 The concept of cooperative ligand-metal C–H bond activation, as exemplified by MPAAs, has become an important design concept in C–H functionalization catalysis.4
Open in a separate windowThis account will focus on our development of MPAA ligands for a diversity of C–H functionalization reactions. First, we will review the pertinent historical background of stoichiometric cyclopalladations and mechanistic studies of Pd-mediated C–H cleavage with external carboxylates. Second, we will summarize the discovery of bifunctional MPAA ligands for catalytic Pd C–H functionalizations and our hypotheses on how MPAAs influence the mechanism of C–H activation. Third, we will present a review of recent literature reports on Pd(II)-catalyzed C(sp2)–H and C(sp3)–H functionalization with MPAA ligands and applications in total synthesis. Finally, we will cover the future outlook for ligand design and reaction development.
The development and application of ligands for facilitating and controlling C–H activation has been the major goal of our research program in Pd(II)-catalyzed C–H functionalization. MPAA ligand acceleration via bifunctional C–H activation has enabled the development of many new Pd(II)-catalyzed C–H functionalization reactions. MPAAs have been instrumental in the development of ligand-accelerated reactions of unreactive substrates, enantioselective C–H activations of both prochiral bonds and symmetrical substrates, as well as site-selective C–H activation. These methods have been applied in a number of total syntheses, demonstrating their practicality and functional group compatibility.
Furthermore, mechanistic studies have identified the key structural elements of MPAAs that influence C–H activation, specifically the bidentate coordination of the carboxylate and amide and the active participation of the N-acyl group in C–H cleavage. Inspired by these insights, we have designed a new generation of ligands derived from amino acids ( ), including N-acyl protected aminomethyl oxazoline (APAO) ligands capable of the highly enantioselective C–H desymmetrization of prochiral methyl groups in isobutyramides,77 mono-N-protected aminoethyl amine (MPAAM) ligands for the enantioselective C–H arylation of cyclopropanecarboxylic and 2-aminoisobutyric acids,78 and mono-N-protected aminoethyl thioether (MPAThio) ligands for enabling the C–H olefination of simple free acids.79 Our lab has also developed related APAQ ligands for the enantioselective arylation of methylene C(sp3)–H bonds, a long-standing challenge in Pd-catalyzed C–H functionalization.80
Open in a separate windowOther research groups have applied MPAA ligands to enable difficult Pd-catalyzed C–H functionalizations, including Martin for the C(sp3)–H lactonization of benzoic acids,81 Gaunt for the C(sp3)–H functionalization of hindered secondary amines82 and C(sp3)–H cross-coupling of tertiary amines,83 You,54, 84 and others.85 In addition, MPAAs derived from β-amino acids, which bind in a six-membered chelate to Pd, have recently been reported as ligands for the arylation86 as well as the highly efficient C(sp3)–H lactonization87 and acetoxylation88 of free acid substrates. Finally, MPAAs have also emerged as promising ligands for achieving high reactivity and selectivity in C–H functionalization with other metals, including Rh(III)89 and Ru(II).90
We believe that MPAA ligands, as well as ligand classes inspired by their structure, could enable the discovery of many new and useful metal-catalyzed C–H functionalization reactions. The discovery and development of MPAAs as ligands for Pd-catalyzed C–H functionalizations is an illustrative example of the power of ligand development for realizing the untapped potential of C–H functionalization as synthetic strategy. As a central challenge in the field, it continues to stimulate and inspire us.
We are indebted to all present and former group members for their invaluable contributions to the work described herein. We gratefully acknowledge TSRI, the NIH (NIGMS, 2R01 GM084019), and Bristol–Meyers Squibb for financial assistance.
Qian Shao received her B.Sc. in Pharmaceutics from Ocean University of China in 2009. In the same year, she moved to Peking University, where she received her Ph.D. in Organic Chemistry under the direction of Prof. Yong Huang. She is currently a postdoctoral fellow in the lab of Prof. Jin-Quan Yu at The Scripps Research Institute.
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Kevin Wu received his B.Sc. in Chemistry from Boston College in 2011, working in Prof. Amir Hoveyda’s lab. He did his Ph.D. studies in Chemistry at Princeton University in Prof. Abigail Doyle’s lab, graduating in 2017. He is currently a postdoctoral scientist in Prof. Jin-Quan Yu’s lab.
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Zhe Zhuang was born in Zhoushan, China. He received predoctoral training in Prof. Wei-Wei Liao’s lab (B.Sc., 2013, Jilin university) and Prof. Zhi-Xiang Yu’s lab (2014–2015, Peking University). He is now a fifth-year graduate student in Prof. Jin-Quan Yu’s lab.
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Shaoqun Qian was born in Shanghai, China. He received predoctoral training in Prof. Renhua Fan’s lab (B.Sc., 2017, Fudan university). He is now a third-year graduate student in Prof. Jin-Quan Yu’s lab.
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Jin-Quan Yu received his B.Sc. in Chemistry from East China Normal University and his M.Sc. from the Guangzhou Institute of Chemistry. In 2000, he obtained his Ph.D. at the University of Cambridge with Prof. Jonathan B. Spencer. After some time as a Junior Research Fellow at Cambridge, he joined the laboratory of Prof. E. J. Corey at Harvard University as a postdoctoral fellow. He then began his independent career at Cambridge (2003–2004), before moving to Brandeis University (2004–2007), and finally The Scripps Research Institute, where he is currently the Frank and Bertha Hupp Professor of Chemistry.
Buchwald-Hartwig amination is a palladium-catalyzed cross-coupling reaction of amines and aryl halides that results in formation of C-N bonds. It was first introduced by Kosugi, Kameyama and Migita in 1983[1]. It was a reaction using 1 mol% PdCl2(P(o-Tolyl3)2 with the addition of aryl bromides and N,N-diethylamino-tributyltin in toluene solvent heated at 100°C for three hours. The resulting data showed that only nonsubstitued bromobenzene would give the product with a high yield.
Scheme 1: Palladium catalyzed C-N cross-coupling reaction
In the following year, Pd(PPh3)4 catalyst mediated -carboline preparation was used to synthesize lavendamycin CDE ring system from 4-aryl pyridines, which was done by Bogen and Panek[2]. After a decade, Hartwig[3] identified and characterized several intermediates in the palladium-catalyzed C-N bond formation. The mechanistic data suggested that the reaction involved oxidation addition and reductive elimination steps.
In the same year, Buchwald[4] published a paper that discussed methods of improving original studies from Migita. One substrate was a volatile amine and the other was an amine with higher boiling point, and the reaction of these two substrates would result in the formation of aminostannes. The transamination was coupled with palladium catalyst to make the reactions available to a broader variety of arylamine substrates.
The catalysis circle is shown in Figure 1. First, Pd(Ⅱ) is reduced to Pd(0) by amines that contain α-H or ligand. Then, Pd kicks one ligand off and undergoes oxidative addition to form Pd(Ⅱ) complex. Next, amines attack Pd, substituting one X under the help of base. The final step is reductive elimination, giving the product and complete the circle. Note that reduction of Pd(Ⅱ) requires amines that contain α-H, otherwise extra ligands should be added to the reaction. An alternative choice is using Pd(0) complex instead of Pd(OAc)2.
Figure 1: Catalytic cycleLigands
Buchwald proposed general ligand design strategy shown below. They changed the functional groups to get a library of ligands, for different substrates. Different ligands will be discussed in detail in Scope part. [5]
Figure 2:Ligand design strategy
Electrophile
RX and ArX
Generally, Br, Cl and I can react with amines in certain conditions. ArI is relatively difficult, unlike other C-C coupling reactions. Mechanism studies showed that this results from the unreactive Pd dimers bridged by iodide anions.[5]
Scheme 1
Toluene is favored for this reaction because of poor solubility of Iodine salt in toluene.
ArOTf, ArONf and ArOMs
ArOTf[6]
ArONf[7]
ArOMs[8]
Scheme 2
OTf, ONf, and OMs broaden the range that Buchwald coupling applies, which means that hydroxyl group can react with amine by using OTf.
Nucleophile
sPrimary amines
Brettphos[9] is the ligand designed for primary amines.
Scheme 3
Figure 3:Structure of Brettphos
Brettphos has selectivity in primary amines toward secondary amines. Using LiHMDS as base combined with Brettphos can get proton tolerance like hydroxyl and carboxyl.
Secondary amines
Everything is almost the same with primary amines, instead of ligand. Ruphos[9] is designed for secondary amines.
Figure 4:Structure of Ruphos
Similarly, LiHMDS is utilized to gain proton tolerance. However, it is not easy to have selectivity in secondary amines toward primary amines by steric hindrance control.
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Amide
[10]
Scheme 4:
Amide is not a good nucleophile, so more reactive ligand tBuBrettpos[10] is designed to solve this problem.
Figure 5:Structure of tBuBrettphos
NH heterocyclic compounds
[11]
Scheme 5
For different types of nucleophile, different ligand is used. For indole, Davephos[11] is a good choice.
Figure 6: Structure of Davephos
Figure 7:structure of tBuXphos
Similarly, tBuXphos[12] is for indazole[13].
Scope
It is critical to choose the correct coordinating ligands to the palladium in the Buchwald-Hartwig amination. For intramolecular coupling reaction of aryl bromides with amines having stereocenters at the α-position to the nitrogen atom, the use of Pd(P(o-tolyl)3) would not give racemic mixtures of products. Instead, it would form products with high enantiopurity. [14]
Scheme 6
However, in the case of intermolecular coupling reactions, it is catalyzed by Pd(BINAP) to give the coupled products without loss of enantioselectivity. [14]
Scheme 7
Choice of base and catalysts
For base and catalysts choice, Buchwald gave a good summary in his “user guide”. We cite it here.[5]
Table 1: Base comparison Base Advantages Disadvantages NaOT-Bu Permits highest reaction rates and lowest catalysis loadings Incompatible with many electrophilic functional groups LHMDSAllows utilization of substrates bearing protic functional groups
Useful for low temperate amination
Solid base is air sensitive
Incompatible with some functional groups at elevated temperature
\(Cs_2CO_3\) Provides excellent functional group tolerance and often highest reaction rate of weak baseExpensive
can be hard to stir on large scale
\(K_3PO_4\) and \(K_3CO_4\)Excellent functional group tolerance
Often most efficient for arylation of amides
Economically attractive
Can require relatively high catalyst loadings and long reactions times Figure 9:Catalyst choice
Advantages and Limitations
Buchwald reactions have many advantages.[5] The catalyst loading is relative low, around 1%-2%, and all ligands are commercially available. It can be done in THF, toluene, t-BuOH and dioxane, and little amount of water is fine. Sometimes water is added intentionally to help Pd(Ⅱ) reduction. Reaction requires argon protected environment, but the reaction system is not very sensitive to oxygen.
As to scope, Buchwald-Hartwig reaction can be applied to various amines, which is discussed above, and most of them have a very good yield. Proton tolerance can be acquired by using LiHMDS. However, functional groups like azo may cause catalyst poisoning, messing the reaction up. Esters and nitro groups are incompatible with KOtBu, but weak base like K2CO3 has a low reaction rate. For more details of this reaction, just turn to Buchwald’s “user guide” published in Chem. Sci. Buchwald-Hartwig reaction is of great significance, which provides a strong tool for C-N coupling.
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D. Bogen and J. Panek, Tetrahedron Lett., 1984, 25, 30, 3175-3178.
F. Paul, J. Patt and J. F. Hartwig, J. Am. Chem. Soc., 1994, 116, 5969-5970.
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