Metal-catalyzed Cross-coupling Research Articles

Why You Really Should Consider Using Palladium-Catalyzed Cross-Coupling of Silanols and Silanolates.

The transition metal-catalyzed cross-coupling of organometallic nucleophiles derived from tin, boron, and zinc with organic electrophiles enjoys a preeminent status among modern synthetic methods for the formation of carbon-carbon bonds. In recent years, organosilanes have emerged as viable alternatives to the conventional reagents, with the added benefits of low cost, low toxicity and high chemical stability. However, silicon-based cross-coupling reactions often require heating in the presence of a fluoride source, which has significantly hampered their widespread acceptance. To address the "fluoride problem", a new paradigm for palladium-catalyzed, silicon-based cross-coupling reactions has been developed that employs a heretofore underutilized class of silicon reagents, the organosilanols. The use of organosilanols, either in the presence of Brønsted bases or as their silanolate salts, represents an operationally simple and mild alternative to the fluoride-based activation method. Organosilanols are readily available by many well-established methods for introducing carbon-silicon bonds onto alkenes, alkynes, arenes and heteroarenes. Moreover, several different protocols for the generation of alkali metal salts of, vinyl-, alkenyl-, alkynyl-, aryl-, and heteroarylsilanolates have been developed and the advantages of each of these methods have been demonstrated for a number of different coupling classes. This review will describe the development and implementation of cross-coupling reactions of organosilanols and their conjugate bases, silanolates, with a wide variety of substrate classes. In addition, application of these transformations in the total synthesis of complex natural products will also be highlighted. Finally, the unique advantages of organosilicon coupling strategies vis a vis organoboron reagents are discussed.

Branched/linear selectivity in palladium-catalyzed allyl-allyl cross-couplings: the role of ligands

While Pd-catalyzed allyl-allyl cross-couplings in the presence of small-bite-angle bidentate ligands reliably furnish the branched regioisomer with high levels of selectivity, cross-couplings in the presence of large-bite-angle bidentate ligands give varying, often unpredictable, levels of selectivity. In a combined computational and experimental study, we probe the underlying features that govern the regioselectivity in these metal-catalyzed cross-couplings.

ChemInform Abstract: Linchpin Dienes: Key Building‐Blocks in the Synthesis of Polyenic Frameworks

AbstractReview: [65 refs.

ChemInform Abstract: Mechanistic Insights into Nickamine‐Catalyzed Alkyl‐Alkyl Cross‐Coupling Reactions

AbstractReview: 9 refs.

Linchpin dienes: key building-blocks in the synthesis of polyenic frameworks.

A myriad of biologically active products incorporates polyenic frameworks. Among the syntheses developed to access these moieties, metal-catalyzed cross-couplings emerged as reactions of choice especially due to their high stereoselectivity. Particularly, the use of bifunctionalized compounds (linchpin reagents) allows a fast, modular and efficient access to polyenic chains. In this review, we will focus on the preparation of bifunctionalized dienes and on their utilization in the synthesis of polyenes.

Nickel-Catalyzed Suzuki-Miyaura Cross-Coupling in a Green Alcohol Solvent for an Undergraduate Organic Chemistry Laboratory.

A modern undergraduate organic chemistry laboratory experiment involving the Suzuki–Miyaura coupling is reported. Although Suzuki–Miyaura couplings typically employ palladium catalysts in environmentally harmful solvents, this experiment features the use of inexpensive nickel catalysis, in addition to a “green” alcohol solvent. The experiment employs heterocyclic substrates, which are important pharmaceutical building blocks. Thus, this laboratory procedure exposes students to a variety of contemporary topics in organic chemistry, including transition metal-catalyzed cross-couplings, green chemistry, and the importance of heterocycles in drug discovery, none of which are well represented in typical undergraduate organic chemistry curricula. The experimental protocol uses commercially available reagents and is useful in both organic and inorganic instructional laboratories.

Mechanistic insights into nickamine-catalyzed alkyl-alkyl cross-coupling reactions.

Within the last decades the transition metal-catalyzed cross-coupling of non-activated alkyl halides has significantly progressed. Within the context of alkyl-alkyl cross-coupling, first row transition metals spanning from iron, over cobalt, nickel, to copper have been successfully applied to catalyze this difficult reaction. The mechanistic understanding of these reactions is still in its infancy. Herein we outline our latest mechanistic studies that explain the efficiency of nickel, in particular nickamine-catalyzed alkyl-alkyl cross-coupling reactions.

Anodic C,C Cross-Coupling Reaction of Aromatic Compounds Using an Electrochemical Flow Microreactor

The C,C cross-coupling reaction of aromatic compounds is important in various fields such as syntheses of ligands, polymers, and natural products contain nonsymmetrical biaryl structures. Therefore, a number of synthetic approaches have been developed1. Typical approaches (such as Negishi coupling and Suzuki-Miyaura coupling) were achieved by using transition metal catalysts and by incorporating leaving functionalities2. Thereby several synthetic steps are needed for the preparation of starting aromatic compounds with leaving functionalities. Reducing these synthetic steps is identical because it leads to reduce the amount of reagent waste. Hence C,H direct activation is cutting edge concept because it doesn't require any special leaving functionalities3. Especially anodic cross-coupling reaction serves as an efficient method that doesn't require transition metal catalysts, leaving functionalities, and also oxidants. Thus it is economically and environmentally attractive. However, when the oxidation potentials of two starting aromatic compounds are near each other, the selective oxidation is hard to conduct. Also, a desired biaryl product suffers from overoxidation because the oxidation potential of the biaryl products are generally lower than that of starting aromatic compounds. As a result, the yield should be decreased. To solve these problems, several approaches were recently developed. For example, Waldvogel and co-workers reported a selective phenol-arene anodic C,C cross-coupling reaction using boron-doped diamond electrodes4. On the other hand, Yoshida and co-workers reported C-H/C-H cross-coupling method using radical cation pools5. Thus, developing efficient anodic cross-coupling reactions is attractive and further investigation is still challenging target. To achieve selective anodic oxidation, we have developed an electrosynthetic system using a pararell laminar flow in a flow microreactor6. Since the channel of flow micrioreactor is narrow, it ensures that the flow is stable and laminar. As shown in Figure 1, when two solutions are introduced through the two inlets (named inlets 1 and 2 in Figure 1), a stable liquid-liquid pararell interface can be formed; mass transfer between input streams occurs only via diffusion. Hence, when a substrate solution is introduced through inlet 1 (anode side) and a nucleophile solution is introduced thorough inlet 2 (cathode side), the substrate is dominantly oxidized to generate a carbocation while oxidation of the nucleophile is avoided. Consequently the carbocation generated at anode rapidly diffuse to the bulk electrolytic solution and react with the nucleophile to afford a desired product. This approach would enable to achieve selective oxidation of aromatic substrates regardless of their oxidation potential. In addition, overoxidation would be avoided because the desired biaryl product would be immediately ejected from reaction field. Thus, this system would overcome existing problems associated with the oxidation potential of substrates and the overoxidation. Figure 2 shows a schematic illustration of the typical 2-inlets flow microreactor for electrosynthetic reaction. The flow microreactor consisted of two plates, which were glued platinum (Pt) plates and glass plate together. A slit was provided on anode side for introducing substrate solutions into the reactor. A spacer was used to leave a rectangular channel exposed, and the two plates were simply sandwiched together. After connecting Teflon tubing to inlets and outlet, the reactor was sealed with epoxy resin. Bulk electrolysis was conducted with a constant current and solution flowing through the electrolysis cell. The flow rate was controlled by using syringe pump. Reaction mixture was collected and then analyzed by HPLC. Consequently, anodic cross-coupling reaction in the flow microreacter resulted in improvement of the current efficiency of 3up to 87 % (scheme 1), while it was 49 % in a batch type reactor. In the presentation, detail of experimental conditions will be discussed.Reference 1 a) Metal-Catalyzed Cross Coupling Reactions, Vol. 1&2 eds, A. de Meijere, et al., Wiley-VCH, Weinheim, 2004 b) G. Bringmann, et. al, Angew Chem. Int. Ed. 2005 44, 5384-5427.2 a) E. Negishi, Acc. Chem. Res. 1982, 15, 340-348 b) N. Miyaura, A. Suzuki, Chem. Rev. 1995, 95, 2457-2483.3 D. Alberico, et al., Chem. Rev. 2007 107, 174-238.4 A. Kirste, et al., Org. Lett. 2011 13, 3127.5 T. Morofuji, et al., Angew Chem. Int. Ed. 2012, 51, 1-5.

Progress of transition metal-catalyzed cross-coupling mediated by PyBroP

In the transition metal-catalyzed cross-coupling reactions, phenol and enol derivatives activated by phosphorus groups are very important electrophiles. This kind of compounds has the advantages of easy preparation, great stability, and producing more benign phosphorus by-products. The present work provides a comprehensive review of the advances made over the past several decades in this area. Cross-coupling reactions mediated by PyBroP are first surveyed, then two types of recently developed transition metal-catalyzed reactions, i.e., Pd-catalyzed and Ni-catalyzed reactions, and the corresponding mechanisms are discussed. Finally, future directions are analyzed.

Metal-Catalyzed Cross-Coupling Reactions of Halomaleic Anhydrides and Halomaleimides: Synthesis of Structurally Interesting and Biologically ­Important Natural and Unnatural Products

This brief review presents a concise literature account of the metal-catalyzed cross-coupling reactions of halomaleic anhydrides and halomaleimides leading to significant synthetic and natural products. Metal-catalyzed Heck, Suzuki–Miyaura, Stille–Migita, Negishi, Hiyama, and Sonogashira cross-coupling reactions with palladium as the key element are discussed. The metal-catalyzed exchange of a vinylic leaving group by a carbon nucleophile, the S_NV reaction, gives a diverse range of bioactive natural and unnatural products.

Recent advances in H-phosphonate chemistry. Part 2. Synthesis of C-phosphonate derivatives.

This chapter provides an overview of recent advances in the development of new methods and protocols for the formation of the P-C bond using H-phosphonate diesters as starting materials. Various chemical and stereochemical aspects of the transition metal-catalyzed cross-coupling and organocatalyst-promoted reactions which are relevant to the synthesis of structurally diverse C-phosphonate derivatives are surveyed.

BippyPhos: A Single Ligand With Unprecedented Scope in the Buchwald–Hartwig Amination of (Hetero)aryl Chlorides

Over the past two decades, considerable attention has been given to the development of new ligands for the palladium-catalyzed arylation of amines and related NH-containing substrates (i.e., Buchwald-Hartwig amination). The generation of structurally diverse ligands, by research groups in both academia and industry, has facilitated the accommodation of sterically and electronically divergent substrates including ammonia, hydrazine, amines, amides, and NH heterocycles. Despite these achievements, problems with catalyst generality persist and access to multiple ligands is necessary to accommodate all of these NH-containing substrates. In our quest to address this significant limitation we identified the BippyPhos/[Pd(cinnamyl)Cl]2 catalyst system as being capable of catalyzing the amination of a variety of functionalized (hetero)aryl chlorides, as well as bromides and tosylates, at moderate to low catalyst loadings. The successful transformations described herein include primary and secondary amines, NH heterocycles, amides, ammonia and hydrazine, thus demonstrating the largest scope in the NH-containing coupling partner reported for a single Pd/ligand catalyst system. We also established BippyPhos/[Pd(cinnamyl)Cl]2 as exhibiting the broadest demonstrated substrate scope for metal-catalyzed cross-coupling of (hetero)aryl chlorides with NH indoles. Furthermore, the remarkable ability of BippyPhos/[Pd(cinnamyl)Cl]2 to catalyze both the selective monoarylation of ammonia and the N-arylation of indoles was exploited in the development of a new one-pot, two-step synthesis of N-aryl heterocycles from ammonia, ortho-alkynylhalo(hetero)arenes and (hetero) aryl halides through tandem N-arylation/hydroamination reactions. Although the scope in the NH-containing coupling partner is broad, BippyPhos/[Pd(cinnamyl)Cl]2 also displays a marked selectivity profile that was exploited in the chemoselective monoarylation of substrates featuring two chemically distinct NH-containing moieties.

ChemInform Abstract: Macrocyclic Drugs and Synthetic Methodologies Toward Macrocycles

AbstractReview: 237 refs.

ChemInform Abstract: Stereoselective Synthesis of All‐Carbon Tetrasubstituted Alkenes from in situ Generated Ketenes and Organometallic Reagents.

Stereoselective synthesis of tetrasubstituted alkenes is a challenging problem in chemical synthesis. New protocols to access this important, yet simple, structural motif are of fundamental significance because they are found in many valuable molecules and can be utilized in a variety of important complexity building chemical transformations. The two-step strategy presented herein involves stereoselective generation of an alkenyl pseudohalide followed by a stereospecific metal-catalyzed cross-coupling.

Macrocyclic drugs and synthetic methodologies toward macrocycles.

Macrocyclic scaffolds are commonly found in bioactive natural products and pharmaceutical molecules. So far, a large number of macrocyclic natural products have been isolated and synthesized. The construction of macrocycles is generally considered as a crucial and challenging step in the synthesis of macrocyclic natural products. Over the last several decades, numerous efforts have been undertaken toward the synthesis of complex naturally occurring macrocycles and great progresses have been made to advance the field of total synthesis. The commonly used synthetic methodologies toward macrocyclization include macrolactonization, macrolactamization, transition metal-catalyzed cross coupling, ring-closing metathesis, and click reaction, among others. Selected recent examples of macrocyclic synthesis of natural products and druglike macrocycles with significant biological relevance are highlighted in each class. The primary goal of this review is to summarize currently used macrocyclic drugs, highlight the therapeutic potential of this underexplored drug class and outline the general synthetic methodologies for the synthesis of macrocycles.

ChemInform Abstract: Suzuki‐Miyaura Cross‐Coupling in Acylation Reactions, Scope and Recent Developments

AbstractReview: 118 refs.

ChemInform Abstract: C—H Arylation of 3‐Substituted Thiophene with Regioselective Deprotonation by TMPMgCl·LiCl and Transition Metal Catalyzed Cross Coupling.

ChemInform Abstract: C—H Arylation of 3‐Substituted Thiophene with Regioselective Deprotonation by TMPMgCl·LiCl and Transition Metal Catalyzed Cross Coupling.

Stereoselective Synthesis of All-Carbon Tetrasubstituted Alkenes from In Situ Generated Ketenes and Organometallic Reagents

Stereoselective synthesis of tetrasubstituted alkenes is a challenging problem in chemical synthesis. New protocols to access this important, yet simple, structural motif are of fundamental significance because they are found in many valuable molecules and can be utilized in a variety of important complexity building chemical transformations. The two-step strategy presented herein involves stereoselective generation of an alkenyl pseudohalide followed by a stereospecific metal-catalyzed cross-coupling.

Electrochemical synthesis of biflavonoids

Biologically active biflavonoids have consistently attracted the attention of researchers [1]. However, only a few of these compounds have a broad spectrum of biological activity. This has prompted scientists to prepare their semi-synthetic and synthetic analogs [2]. Thus, several approaches including metal-catalyzed cross coupling, oxidative coupling, Ulmann condensation with nucleophiles, etc. have been used to synthesize biflavonoids [2]. We hypothesized that it would be possible to use an electrochemical method to prepare novel compounds based on flavonoids [3–5]. The flavonols isorhamnetin and kaempferide that were isolated earlier by us from Alhagi pseudalhagi (M. Bieb.) Fisch. were used for the synthesis. The flavonol (1 mmol) was dissolved in CH3CN (100 mL). The electrolysis was carried out in the presence of LiClO4 (0.1 M) in a cell with a diaphragm and a Pt anode of working surface 2 cm 2 and current density 5 mA/cm2 for 3 h. When the electrolysis was finished, about 90% of the solvent was distilled off. The remainder was used to separate the products by column chromatography over silica gel. In both instances, the principal products were recrystallized from acetone to afford light-brown powders in 0.22 ± 0.05 g yields. Their physicochemical and spectral characteristics were determined by known methods. Compound 1. C32H22O14, mp 285 ± 3°C, [ ]D 20 +39.7° (c 0.57, MeOH). UV spectrum (MeOH, max, nm): 251, 325, 356. IR spectrum (KBr, max, cm –1): 3430, 3370 (OH), 1681, 1600 (C=O), 1607, 1570 (aromatic C=C). Mass spectrum (EI, 70 eV), m/z (Irel, %): 630 (M +, 100), 615 (13), 315 (17). PMR spectrum (400 MHz, CDCl3, , ppm): 3.96 (6H, d, 3 , 3 -OCH3), 6.83 (2H, s, H-6, 6 ), 7.23 (2H, s, H-5 , 5 ), 7.52 (4H, s, H-2 , 6 , 2 , 6 ), 9.35 (2H, s, OH-4 , 4 ), 10.12 (2H, s, OH-7, 7 ), 10.82 (2H, s, OH-3, 3 ), 12.10 (2H, s, OH-5, 5 ). Compound 2. C32H20O12, mp 291 ± 3°C, [ ]D 20 +38.4° (c 0.52, MeOH). UV spectrum (MeOH, max, nm): 210, 271, 368. IR spectrum (KBr, max, cm –1): 3423 (OH), 1590 (C=O), 1520, 1460 (aromatic C=C). Mass spectrum (EI, 70 eV), m/z (Irel, %): 596 (M +, 100), 581 (12), 298 (22). PMR spectrum (400 MHz, CDCl3, , ppm): 3.83 (6H, d, OCH3-4 , 4 ), 6.83 (2H, s, H-6, 6 ), 7.36 (4H, s, H-3 , 3 , 5 , 5 ), 7.50 (4H, s, H-2 , 6 , 2 , 6 ), 10.16 (2H, s, OH-7, 7 ), 10.76 (2H, s, OH-3, 3 ), 12.17 (2H, s, OH-5, 5 ).

Suzuki-Miyaura Cross-Coupling in Acylation Reactions, Scope and Recent Developments

Since the first report and due to its handiness and wide scope, the Suzuki-Miyaura (SM) cross coupling reaction has become a routine methodology in many laboratories worldwide. With respect to other common transition metal catalyzed cross couplings, the SM reaction has been so far less exploited as a tool to introduce an acyl function into a specific substrate. In this review, the various approaches found in the literature will be considered, starting from the direct SM acylative coupling to the recent developments of cross coupling between boronates and acyl chlorides or anhydrides. Special attention will be dedicated to the use of masked acyl boronates, alkoxy styryl and alkoxy dienyl boronates as coupling partners. A final section will be then focused on the acyl SM reaction as key synthetic step in the framework of natural products synthesis.