mono-N-protected Amino Acid Research Articles

Roles of Ligand and Oxidant in Pd(II)-Catalyzed and Ligand-Enabled C(sp3)–H Lactonization in Aliphatic Carboxylic Acid: Mechanistic Studies

The mechanism of Pd(II)-catalyzed, mono-N-protected amino acid (MPAA) ligand and TBHP oxidant-mediated lactonization of β-C(sp3)–H bond in aliphatic carboxylic acid has been studied. We have shown that the combination of TBHP oxidant and MPAA ligand is very critical: the reaction proceeds via MPAA ligand-mediated Pd(II)/Pd(IV) oxidation by TBHP, followed by C–O reductive elimination from the Pd(IV) intermediate. While Pd(II)/Pd(IV) oxidation is a rate-limiting step, C–H bond activation is the regioselectivity-controlling step. MPAA ligand acts not only as an auxiliary ligand to stabilize the catalytic active species but also as a proton acceptor in C–H bond deprotonation and as a proton donor during Pd(II)/Pd(IV) oxidation by TBHP. The use of a peroxide-based oxidant with the hydroxyl group is required: in the rate-limiting Pd(II)/Pd(IV) oxidation transition state, the H-atom of the OH group participates in the 1,2-hydrogen shift to facilitate proton-shuttling between MPAA ligand and peroxide. Thus, lactonization of the C(sp3)–H bond in aliphatic carboxylic acid occurs via the Pd(II)/Pd(IV) catalytic cycle, unlike the previously reported Pd(II)-catalyzed pyridone ligand and O2 oxidant-assisted benzylic C–H lactonization in aromatic o-methyl benzoic acid, which occurs via the Pd(II)/Pd(0) catalytic cycle and an intramolecular SN2 nucleophilic substitution mechanism. A comparison of these findings for C(sp3)–H bond lactonization in aliphatic and aromatic carboxylic acids enabled us to identify the roles of catalyst, substrate, ligand, and oxidant.

Mechanistic Investigation of Palladium-Catalyzed meta-C-H Bond Activation of Arenes with a Carboxyl Directing Group.

The mechanism of Pd(II)-catalyzed meta-C-H bond olefination of arenes with a carboxyl directing group (DG)-containing template has been investigated with density functional theory. The reaction includes three major steps: C-H bond activation, alkene insertion, and β-hydride elimination. The C-H activation step, which proceeds via a concerted metalation-deprotonation pathway, is found to be the rate- and regioselectivity-determining step. We proposed a mono-N-protected amino acid (MPAA)/DG-assisted C-H activation model, in which the carboxyl DG coordinates with the Pd center and delivers it to the meta-position of arene, and the bidentate dianionic MPAA acts as a base for deprotonation. There is a hydrogen bonding interaction between the carboxyl DG and the carboxylate group of MPAA. An alternative Pd(OAc)2-catalyzed mechanism without involvement of MPAA is also operative. The template is conformationally flexible, and multiple low-energy transition-state conformations contribute to the regioselectivity.

Distal γ-C(sp3 )-H Olefination of Ketone Derivatives and Free Carboxylic Acids.

Reported herein is the distal γ-C(sp3 )-H olefination of ketone derivatives and free carboxylic acids. Fine tuning of a previously reported imino-acid directing group and using the ligand combination of a mono-N-protected amino acid (MPAA) and an electron-deficient 2-pyridone were critical for the γ-C(sp3 )-H olefination of ketone substrates. In addition, MPAAs enabled the γ-C(sp3 )-H olefination of free carboxylic acids to form diverse six-membered lactones. Besides alkyl carboxylic acids, benzylic C(sp3 )-H bonds also could be functionalized to form 3,4-dihydroisocoumarin structures in a single step from 2-methyl benzoic acid derivatives. The utility of these protocols was demonstrated in large scale reactions and diversification of the γ-C(sp3 )-H olefinated products.

Distal γ‐C(sp3)−H Olefination of Ketone Derivatives and Free Carboxylic Acids

AbstractReported herein is the distal γ‐C(sp3)−H olefination of ketone derivatives and free carboxylic acids. Fine tuning of a previously reported imino‐acid directing group and using the ligand combination of a mono‐N‐protected amino acid (MPAA) and an electron‐deficient 2‐pyridone were critical for the γ‐C(sp3)−H olefination of ketone substrates. In addition, MPAAs enabled the γ‐C(sp3)−H olefination of free carboxylic acids to form diverse six‐membered lactones. Besides alkyl carboxylic acids, benzylic C(sp3)−H bonds also could be functionalized to form 3,4‐dihydroisocoumarin structures in a single step from 2‐methyl benzoic acid derivatives. The utility of these protocols was demonstrated in large scale reactions and diversification of the γ‐C(sp3)−H olefinated products.

Catalytic Behavior of Mono-N-Protected Amino-Acid Ligands in Ligand-Accelerated C-H Activation by Palladium(II).

Mono-N-protected amino acids (MPAAs) are increasingly common ligands in Pd-catalyzed C-H functionalization reactions. Previous studies have shown how these ligands accelerate catalytic turnover by facilitating the C-H activation step. Here, it is shown that MPAA ligands exhibit a second property commonly associated with ligand-accelerated catalysis: the ability to support catalytic turnover at substoichiometric ligand-to-metal ratios. This catalytic role of the MPAA ligand is characterized in stoichiometric C-H activation and catalytic C-H functionalization reactions. Palladacycle formation with substrates bearing carboxylate and pyridine directing groups exhibit a 50-100-fold increase in rate when only 0.05 equivalents of MPAA are present relative to PdII . These and other mechanistic data indicate that facile exchange between MPAAs and anionic ligands coordinated to PdII enables a single MPAA to support C-H activation at multiple PdII centers.

From Pd(OAc)2 to Chiral Catalysts: The Discovery and Development of Bifunctional Mono-N-Protected Amino Acid Ligands for Diverse C-H Functionalization Reactions.

The functionalization of unactivated carbon-hydrogen 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 toward the realization of transformations that 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 is especially attractive as a catalyst for such C-H functionalizations because of 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 perform only 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 toward 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 with excellent stereoselectivity when applicable. Mechanistic studies indicate that MPAAs operate as unique bifunctional ligands 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.

Late-Stage Modification of Tertiary Phosphines via Ruthenium(II)-Catalyzed C-H Alkylation.

Ru(II)-catalyzed direct alkylation of tertiary phosphines via hydroarylation of activated olefins promoted by mono-N-protected amino acid (MPAA) was achieved. This protocol provides a straightforward access to a large library of Buchwald-type bulky alkylated monophosphines from commercially available biaryl phosphine. Moreover, two ruthenacycle intermediates of tertiary phosphines via C-H bond cleavage were isolated to illustrate the mechanism of P(III)-directed C-H activation.

Weak coordinated nitrogen functionality enabled regioselective C-H alkynylation via Pd(II)/mono-N-protected amino acid catalysis.

The exploration of weak coordinated amine derivative enabled regioselective C-H functionalization remains challenging due to the elusive achievement of reactivity and selectivity simultaneously. Herein, regioselective C-H alkynylation of various readily transformable nitrogen functionalities was developed with great efficiency, with the assistance of the mono-N-protected amino acid (MPAA) ligand via Pd(ii) catalysis proceeding via 5, 6 and 7-membered palladacycle intermediates.

Ligand Promoted, Palladium-Catalyzed C(sp2)-H Arylation of Free Primary 2-Phenylethylamines.

A mono- N-protected amino acid (MPAA) ligand promoted, Pd(II)-catalyzed C(sp2)-H arylation of free primary 2-phenylethylamines using the native NH2 as the directing group has been achieved. This method is compatible with challenging simple primary 2-phenylethylamines bearing α-hydrogen atoms. Application of this protocol in the direct structure modification of the drug molecule amphetamine is also demonstrated.

Experimental-Computational Synergy for Selective Pd(II)-Catalyzed C-H Activation of Aryl and Alkyl Groups.

C-H activation and functionalization are on the forefront of modern synthetic chemistry. Imagine if any C-H bond of a molecule could be converted to a C-X bond, where X is the target functionality-this would alter the synthetic blueprints for complex target molecules since it would provide novel disconnections in retrosynthetic analysis. Collaborations between many experimental and computational groups have led to rapid developments of new C-H functionalization methods. Our groups represent an example of this; we were brought together as part of the NSF-supported Center for Selective C-H Functionalization. Many examples of experimental-computational synergy for selective Pd(II)-catalyzed C-H activation of aryl and alkyl groups are described in this Account. We describe computations by the Houk group made in response to experimental stimuli by the Yu group. The first section discusses the experimental and computational investigations of oxazoline-directed stereoselective Pd(II)-catalyzed C(sp3)-H bond activation that occurs through the concerted metalation-deprotonation (CMD) pathway involving a monomeric Pd(II) complex. The second section involves two types of bidentate ligands, mono-N-protected amino acid (MPAA) and acetyl-protected aminoethyl quinoline (APAQ) ligands that promote the C-H activation reactions with the ligand as the internal base. In the MPAA-assisted remote C-H bond activation, the basic dianionic amidate ligand participates in the deprotonation of a specific C-H bond. This mechanism accounts for the improved reactivity and selectivity in C-H activation reactions with MPAA ligands. The chiral APAQ ligands enable asymmetric palladium insertion into prochiral C-H bonds on a single methylene carbon center. The dianionic amidate of the APAQ ligand acts as an intramolecular base to deprotonate the methylene C-H asymmetrically and facilitate chiral Pd-C bond formation. The origins of the dramatic differences of five-membered (relatively inactive) and six-membered (highly active) chelation in β-methylene C(sp3)-H activation reactions by a Pd(II) catalyst were explained with density functional theory (DFT) calculations. This is mainly due to the steric repulsions between the ArF group of the substrate and the quinoline group of the ligand. The steric repulsion between the ArF group of the substrate and the quinoline group of the APAQ ligand destabilizes the five-membered chelate transition structure, increasing the energy of the transition state. The third section discusses a mechanism involving a Pd-Ag heterodimeric complex intermediate in the template-directed, Pd(II)-catalyzed remote meta functionalization of toluene derivatives and benzoic acid derivatives. The nitrile directing group of the template coordinates with Ag while the Pd is placed adjacent to the meta-C-H bond in the transition state, leading to the observed high meta selectivity. The selective activation of remote meta-C-H bonds at various distances can be achieved by tuning the template. The dual role of AgOAc as both an oxidant and part of the heteronuclear active species in the mechanism involving PdAg(OAc)3 was determined by DFT calculations and is in accord with literature information about complexes. For the systems discussed in these three sections, the similarity is that they all proceed via the CMD mechanism. The differences lie in the proton acceptors and the active Pd species. Common CMD involves a monomeric Pd mechanism with acetate as the proton acceptor. Both MPAA and APAQ ligands react via monomeric Pd mechanisms with a ligand moiety (the amidate oxygen) as the proton acceptor. Nitrile-containing template-mediated meta-C-H activations proceed via a Pd-Ag heterodimeric mechanism, still with acetate as the proton acceptor. The interaction between our two groups, experts in experiment and computation, and the discoveries made possible by that interplay are highlighted in this Account.

Ligand-Enabled γ-C(sp3)–H Cross-Coupling of Nosyl-Protected Amines with Aryl- and Alkylboron Reagents

Pd(II)-catalyzed γ-C(sp3)–H cross-coupling of 4-nitrobenzenesulfonyl (Ns)-protected amines is realized using both arylboron and alkylboron coupling partners. An acetyl-protected aminomethyl oxazoline (APAO) ligand is found to enable the C(sp3)–H arylation reaction, whereas mono-N-protected amino acid (MPAA) ligands promote the C(sp3)–H cross-coupling with various alkylboron reagents. Notably, the APAO-promoted C–H arylation reactions afford high diastereoselectivity (>20:1), providing a useful method for modifying chiral amines. The use of a common nosyl protecting group to direct C(sp3)–H activation significantly improves the practicality of this transformation, as demonstrated by the gram-scale stereoselective synthesis of γ-aryl- and γ-alkyl-α-amino acids.

Enantioselectivity Model for Pd-Catalyzed C–H Functionalization Mediated by the Mono-N-protected Amino Acid (MPAA) Family of Ligands

The mono-N-protected amino acid (MPAA) family of ligands is arguably the most prolific scaffold for enabling enantioselective C–H activation via metal insertion. However, its mechanism for asymmetric induction is not fully understood. Here, we developed a practical model for asymmetric induction from the viewpoint of rationalizing chiral, bidentate ligands for C–H activation via metal insertion. The model is validated against Pd(II)-catalyzed C–H activation in 2-benzhydrylpyridine mediated by the [(cyclohexyloxy)carbonyl]-l-leucine (MPAA) ligand. We found that full control elements of enantioselectivity are (a) inherent strain in the bidentate coordination of substrate and the ability of the ligand to enhance it, (b) the gearing effect that restricts the C–H bond activation to one face of the Pd catalyst, (c) potential interactions between the ligand and substrate, and (d) chelate inversion which is controlled by the ligand-anchored base that restricts the C–H bond activation to one side of the Pd catalys...

ChemInform Abstract: The Mechanism of Palladium(II)‐Mediated C—H Cleavage with Mono‐N‐Protected Amino Acid (MPAA) Ligands: Origins of Rate Acceleration

AbstractReview: 155 refs.

The mechanism of palladium(II)-mediated C–H cleavage with mono-N-protected amino acid (MPAA) ligands: origins of rate acceleration

Abstract It has long been known that transition metals are capable of interacting with, cleaving, and mediating the functionalization of activated and unactivated carbon–hydrogen (C–H) bonds. Broadly speaking, a basic underlying principle in the fields of inorganic and organometallic chemistry is that the primary and secondary coordination spheres around a metal affect its reactivity and selectivity in elementary reactions. Hence, ligand design in transition metal catalysis has been a captivating area of research for over half a century. The discovery and development of novel ligands to promote and control otherwise recalcitrant C–H functionalization reactions is now at the forefront of organic and organometallic chemistry. Central to this line of inquiry is the interplay between ligand, substrate, metal, and reaction mechanism. This Review highlights the mechanistic details of palladium(II)-mediated C–H cleavage with mono-N-protected amino acid (MPAA) ligands. Relevant historical background is discussed, the key discoveries in catalysis with MPAAs are examined, experimental and computational studies to elucidate reaction mechanisms are presented, and possible future directions are described.

Ligand-Promoted Pd(II)-Catalyzed Functionalization of Unactivated C(sp3)–H Bond: Regio- and Stereoselective Synthesis of Arylated Rimantadine Derivatives

Stereoselective functionalization of the adamantyl bridge methylene C(sp3)–H bonds is a rather appealing, yet challenging strategy due to the bulky and unactivated nature. Here we present a palladium-catalyzed C(sp3)–H arylation/hetereoarylation of the antivirus drug rimantadine with the picolinamide moiety as the bidentate directing group and a mono-N-protected amino acid (MPAA) as the ligand. Multisubstituted rimantadine substrates and diverse aryl/heteroaryl iodides are well tolerated, and a series of optically pure arylated rimantadine derivatives have been synthesized in high regio- and diastereoselectivity that provides ample compound space for further pharmaceutical research.

Enantioselective ortho-C-H cross-coupling of diarylmethylamines with organoborons.

The commonly used para-nitrobenzenesulfonyl (nosyl) protecting group is employed to direct the CH activation of amines for the first time. An enantioselective ortho-CH cross-coupling between nosyl-protected diarylmethylamines and arylboronic acid pinacol esters has been achieved utilizing chiral mono-N-protected amino acid (MPAA) ligands as a promoter.

Enantioselective ortho‐CH Cross‐Coupling of Diarylmethylamines with Organoborons

AbstractThe commonly used para‐nitrobenzenesulfonyl (nosyl) protecting group is employed to direct the CH activation of amines for the first time. An enantioselective ortho‐CH cross‐coupling between nosyl‐protected diarylmethylamines and arylboronic acid pinacol esters has been achieved utilizing chiral mono‐N‐protected amino acid (MPAA) ligands as a promoter.

Palladium(II)-Catalyzed Highly Enantioselective C–H Arylation of Cyclopropylmethylamines

C-H arylation via a Pd(II)/Pd(IV) catalytic cycle has been one of the most extensively studied C-H activation reactions since the 1990s. Despite the rapid development of this reaction in the past two decades, an enantioselective version has not been reported to date. Herein, we report a Pd(II)-catalyzed highly enantioselective (up to 99.5% ee) arylation of cyclopropyl C-H bonds with aryl iodides using mono-N-protected amino acid (MPAA) ligands, providing a new route for the preparation of chiral cis-aryl-cyclopropylmethylamines. The enantiocontrol is also shown to override the diastereoselectivity of chiral substrates.

Factors Impacting the Mechanism of the Mono-N-Protected Amino Acid Ligand-Assisted and Directing-Group-Mediated C–H Activation Catalyzed by Pd(II) Complex

We computationally studied the roles of the (a) protecting group (PG), (b) side chain (R), and (c) length of amino acid backbone of the mono-N-protected amino acid (MPAA) ligand as well as (d) the nature of the substrate (DG-SUB) and directing group (DG) on the following elementary steps of the “N–H bond cleavage and subsequent C–H bond activation” mechanism for [MPAA]–Pd(II)-catalyzed C–H activation: (i) formation of the prereaction complex, [MPAA]–Pd(II)–[DG-SUB], with a weakly coordinated monoanionic amino acid ligand; (ii) N–H bond cleavage and formation of the catalytically active intermediate, [MPAA′]–Pd(II)–[DG-SUB], with a bidentately coordinated dianionic amino acid ligand, and (iii) C–H bond activation in [MPAA′]–Pd(II)–[DG-SUB] occurring via the concerted metalation/deprotonation pathways A (outer-sphere) and B (inner-sphere). For the prereaction complex, we find that weak coordination of the MPAA ligand to Pd(II) is affected by (a) the strong electron-withdrawing ability of the PG, (b) longer ...