The promise and challenge of iron-catalyzed cross coupling

Transition metal catalysts, particularly those derived from the group VIII-X metals, display remarkable efficiency for the formation of carbon-carbon and carbon-heteroatom bonds through the reactions of suitable nucleophiles with organic electrophilic partners. Within this subset of the periodic table, palladium and nickel complexes offer the broadest utility, while additionally providing the deepest mechanistic insight into thus-termed "cross-coupling reactions". The mammoth effort devoted to palladium and nickel catalysts over the past 30 years has somewhat obscured reports of alternative metal complexes in this arena. As cross-coupling reactions have evolved into a critical support for modern synthetic chemistry, the search for alternative catalysts has been taken up with renewed vigor.When the current generation of synthetic chemists reflects back to the origins of cross coupling for inspiration, the well-documented effect of iron salts on the reactivity of Grignard reagents with organic electrophiles surfaces as a fertile ground for alternative catalyst development. Iron possesses the practical benefits more befitting an alkali or alkaline earth metal, while displaying the unique reactivity of a d-block element. Therefore the search for broadly applicable iron catalysts for cross coupling is an increasingly important goal in modern synthetic organic chemistry.This Account describes the evolution of iron-catalyzed cross coupling from its inception in the work of Kochi to the present. Specific emphasis is placed on reactivity and synthetic applications, with selected examples from acyl-, alkenyl-, aryl-, and alkyl halide/pseudohalide cross coupling included. The typical reaction partners are Grignard reagents, though organomanganese, -copper, and -zinc derivatives have also been used in certain cases. Such iron-catalyzed processes occur very rapidly even at low temperature and therefore are distinguished by broad functional group compatibility. Furthermore, recent advances in carbon-heteroatom bond formation and studies relevant to the general reactivity of in situ generated and structurally defined "low-valent" iron catalysts are presented.The preparative aspects of iron-catalyzed cross coupling are encouraging, but the inclination to classify these processes within the characteristic reaction manifold is premature, as mechanistic studies have evolved at a comparatively slow pace. A typical protocol for cross coupling employs an Fe(+2) or Fe(+3) precatalyst, which is reduced in situ by the organometallic nucleophile. The nature of the resulting active component(s) is still best described, more than 30 years later, in Kochi's original terms as a "reduced form of soluble iron". Despite huge gaps in our current knowledge, three distinct mechanisms have been formulated, largely based on empirical evidence: a "canonical" cross-coupling process, a manifold wherein alkylation of an organoiron intermediate replaces transmetalation as a key step, and finally a proposal reliant on the formation of nucleophilic ate complexes. Conjecture and speculation abound, but precisely what constitutes the catalytic cycle in iron-catalyzed cross coupling remains an extremely challenging unanswered question.     

Cross-coupling reaction of alkyl halides with grignard reagents catalyzed by Ni, Pd, or Cu complexes with pi-carbon ligand(s)

Transition metal-catalyzed cross-coupling reactions of organic halides and pseudo-halides containing a C-X bond (X = I, Br, Cl, OTf, OTs, etc.) with organometallic reagents are among the most important transformations for carbon-carbon bond formation between a variety of sp, sp(2), and sp(3)-hybridized carbon atoms. In particular, researchers have widely employed Ni- and Pd-catalyzed cross-coupling to synthesize complex organic structures from readily available components. The catalytic cycle of this process comprises oxidative addition, transmetalation, and reductive elimination steps. In these reactions, various organometallic reagents could bear a variety of R groups (alkyl, vinyl, aryl, or allyl), but the coupling partner has been primarily limited to sp and sp(2) carbon compounds: alkynes, alkenes, and arenes. With alkyl coupling partners, these reactions typically run into two problems within the catalytic cycle. First, oxidative addition of alkyl halides to a metal catalyst is generally less efficient than that of aryl or alkenyl compounds. Second, the alkylmetal intermediates formed tend to undergo intramolecular beta-hydrogen elimination. In this Account, we describe our efforts to overcome these problems for Ni and Pd chemistry. We have developed new catalytic systems that do not involve M(0) species but proceed via an anionic complex as the key intermediate. For example, we developed a unique cross-coupling reaction of alkyl halides with organomagnesium or organozinc reagents catalyzed by using a 1,3-butadiene as the additive. This reaction follows a new catalytic pathway: the Ni or Pd catalyst reacts first with R-MgX to form an anionic complex, which then reacts with alkyl halides. Bis-dienes were also effective additives for the Ni-catalyzed cross-coupling reaction of organozinc reagents with alkyl halides. This catalytic system tolerates a wide variety of functional groups, including nitriles, ketones, amides, and esters. In addition, we have extended the utility of Cu-catalyzed cross-coupling reactions. With 1-phenylpropyne as an additive, Cu-catalyzed reactions of alkyl chlorides, fluorides, and mesylates with Grignard reagents proceed efficiently. These new catalytic reactions use pi-carbon ligands such as pi-allyl units or alkynes instead of heteroatom ligands such as phosphines or amines. Overall, these reactions provide new methodology for introducing alkyl moieties into organic molecules.     

Catalytic enantioselective conjugate addition with Grignard reagents

In this Account, recent advances in catalytic asymmetric conjugate addition of Grignard reagents are discussed. Synthetic methodology to perform highly enantioselective Cu-catalyzed conjugate addition of Grignard reagents to cyclic enones with ee's up to 96% was reported in 2004 from our laboratories. Excellent levels of stereocontrol were achieved with Cu(I) halides, alkylmagnesium bromides, and commercially available chiral ferrocenyl diphosphines. Studies carried out during the last 2 years demonstrated that these Cu-catalysts are very effective for the enantioselective conjugate addition of Grignard reagents to acyclic enones, alpha,beta-unsaturated esters, and thioesters. On the basis of this methodology, a diastereo- and enantioselective iterative route to deoxypropionate units was developed and applied to the synthesis of natural products. Finally, we summarize our recently conducted mechanistic investigations and the application of this catalytic system to the enantioselective SN2' substitution reactions of allylic bromides with Grignard reagents.     

Rapid analysis of jojoba wax fatty acids and alcohols after derivatization using Grignard reagents

This method, based on the action of Grignard reagents, is an original approach to wax derivatization and differs from the methods previously described, which were essentially based on wax alcoholysis. Grignard reagents, especially magnesium ethyl bromide, react on ester functions to turn the wax constituents into primary and tertiary alcohols, the latter being the fatty acid derivatives. The mixture of these alcohols is analyzed by a single gas chromatographic injection. The overall time, about 1.5 hr, makes this method suitable for routine analysis. It could be also considered for analyzing low carbon condensation organic acid esters.     

Synthesis and structural characterization of a trispyrrole iron(II) complex K(dme)4[tpaMesFe] and application in nitrous oxide dependent coupling reactions

A new synthetic route to the trispyrrole iron(II) complex {K(dme)₄[tpa^MesFe]} was established starting from BOC-protected pyrrol via synthesis of the corresponding boronic acid, cross-coupling reaction, deprotection, triple Mannich reaction, a deprotonation and finally a salt metathesis. The complex was characterized and applied in iron-catalyzed coupling reactions. In more detail, with catalytic amounts of K(dme)₄[tpa^MesFe] the homo-coupling of aromatic Grignard reagents as well as the hetero-coupling of aromatic Grignard reagents were feasible. Noteworthy, to force the reaction nitrous oxide was added to realize yields up to 93% at mild reaction conditions.     

Monofunktionalisierte Dendrons verschiedener Generationen – als Reagenzien zur Einführung dendritischer Reste

Monofunctionalized Dendrons of Different Generations – as Reagents for the Introduction of Dendritic Substituents In recent years dendrimers become more and more important not only in organic chemistry. They represent a new class of molecules with unique characteristic features. But dendrimers represent not only designed molecular architecture. They stand for a new concept in chemistry. They can be used to alter the properties of already existing molecular skeletons or they can be used to transfer new properties to a classical functional unit. This means that functionalized dendrimers and dendrons (dendritic building blocks) can be regarded as reagents for the preparation of new compounds with dendritic properties. In this article the synthesis and the practical use of appropriate dendritic reagents is explained. Furthermore we introduce the new technical terms „{n} dendryl-”︁ for dendritic substituents of n generations and „dendriagent”︁ which stands for dendritic reagents. Moreover we give a short outlook on future developments.     

Gold Catalysis and Fluorine

Performing gold-catalyzed organic transformations in the presence of fluorinating reagents can lead to both fluorinated and non-fluorinated products. Gold(I) complexes can activate alkynes towards nucleophilic attack by fluoride leading to fluoroalkenes under mild conditions. Fluorinated products can also be prepared upon performing gold-catalyzed transformations in the presence of electrophilic sources of fluorine. In most cases, however, the combination of gold and electrophilic fluorinating reagents does not lead to fluorination but delivers products of oxidative homo- or cross-coupling. In these processes the “F⁺” source is likely acting as a sacrificial two-electron external oxidant performing the key oxidation of gold(I) to gold(III) in the redox cycle. Oxidative coupling is an emerging field of gold catalysis which, when combined with the well-established reactivity of gold as a soft π-acid, holds promise as a mild and efficient method for the construction of complex organic molecules.     

过渡金属催化下的格氏试剂与卤代烃的偶联反应研究进展

格氏试剂与卤代烃的偶联反应是有机合成中形成C-C健的重要方法.详细介绍了各种过渡金属催化下的偶联反应,从机理、过程和方法上进行了探讨,并展望该领域未来的发展方向.     

The Development of Alkoxide-Directed Metallacycle-Mediated Annulative Cross-Coupling Chemistry

Alkoxide-directed metallacycle-mediated cross-coupling is a rapidly growing area of reaction methodology in organic chemistry. Over the last decade, developments have resulted in more than thirty new and highly selective intermolecular (or “convergent”) C−C bond-forming reactions that have established powerful retrosynthetic relationships in stereoselective synthesis. While early studies were focused on developing transformations that forge a single C−C bond by way of a functionalized and unsaturated metallacyclopentane intermediate, recent advances mark the ability to employ this organometallic intermediate in additional stereoselective transformations. Among these more advanced coupling processes, those that embrace the metallacycle in subsequent [4+2] chemistry have resulted in the realization of a number of highly selective annulative cross-coupling reactions that deliver densely functionalized and angularly substituted carbocycles. This review discusses the early development of this chemistry, recent advances in reaction methodology, and shares a glimpse of the power of these processes in natural product synthesis.     

SiliaCat ® TEMPO: An Effective and Recyclable Oxidizing Catalyst

Organically modified silica-based SiliaCat TEMPO is an oxidizing catalyst that can efficiently replace other homogeneous stable nitroxyl radicals. Its high activity, reusability, leach-proof properties, selectivity towards the oxidation of alcohols into aldehydes/ketones and its capacity to carry out the oxidation in either organic solvents or water, with or without KBr as co-catalyst, have shown that this material is green chemistry driven.     

Phosphoramidites: marvellous ligands in catalytic asymmetric conjugate addition

The development of an efficient catalytic system for enantioselective carbon-carbon bond formation by 1,4-addition of organometallic reagents (organolithium, Grignard, and organozinc reagents) to enones is a major challenge in organic synthesis. This Account presents the breakthrough realized in this field using chiral phosphoramidite ligands for copper-catalyzed dialkylzinc additions. Applications in catalytic routes to cycloalkanones as well as tandem and annulation procedures with excellent enantioselectivities are discussed.     

Cross-coupling of C(sp)-H Bonds with Organometallic Reagents via Pd(II)/Pd(0) Catalysis**

Palladium-catalyzed C-H activation/C-C bond-forming reactions have emerged as a promising class of synthetic tools in organic chemistry. Among the many different means of forging C-C bonds using Pd-mediated C-H activation, a new horizon in this field is Pd(II)-catalyzed cross-coupling of C-H bonds with organometallic reagents via a Pd(II)/Pd(0) catalytic cycle. While this type of reaction has proven to be effective for the selective functionalization of aryl C(sp(2))-H bonds, the focus of this review is on Pd(II)-catalyzed C(sp(3))-H activation/C-C cross-coupling, a topic of particular importance because reactions of this type enable fundamentally new methods for bond construction. Since our laboratory's initial report on cross-coupling of C-H bonds in 2006, this area has expanded rapidly, and the unique ability of Pd(II) catalysts to cleave and functionalize alkyl C(sp(3))-H bonds has been exploited to develop protocols for forming an array of C(sp(3))-C(sp(2)) and C(sp(3))-C(sp(3)) bonds. Furthermore, enantioselective C(sp(3))-H activation/C-C cross-coupling has been achieved through the use of chiral amino acid-derived ligands, offering a novel technique for producing enantioenriched molecules. Although this nascent field remains at an early stage of development, further investigations hold the potential to revolutionalize the way in which chiral molecules are synthesized in industrial and academic laboratories.     

Pd催化芳基重氮盐的Suzuki偶联反应研究进展

综述了不同Pd催化剂催化的芳基重氮盐的Suzuki偶联反应,并对其优缺点进行了比较,同时对Suzuki偶联反应的应用进行了阐述。     

Copper(I)‐Mediated Highly Stereoselective syn‐Carbometalation of Secondary or Tertiary Propargylic Alcohols with Primary Grignard Reagents in Toluene with a High Linear Regioselectivity

A highly regio‐ and stereoselective syn‐carbometalation of terminal secondary or tertiary propargylic alcohols with primary alkyl Grignard reagents in toluene or phenylmagnesium bromide in Et₂O was developed, in which the alkyl or phenyl group from the Grignard reagents is introduced into the terminal position of the alcohols. The organometallic intermediate formed may be used directly for the coupling reaction with organic halides. Upon treatment with I₂ after the carbometalation, iodides may be obtained, which may undergo Sonogashira coupling reaction and highly stereoselective Novozym‐435‐catalyzed kinetic resolution to afford the optically active products.     

金属试剂参与的α,β-不饱和羰基化合物的不对称共轭加成反应研究进展

α,β-不饱和化合物尤其是羰基化合物的不对称共轭加成反应在有机合成中是一类非常重要的反应。文章综述了格氏试剂、锌试剂以及芳基金属试剂和α,β-不饱和羰基化合物在铜或镍的催化作用下的不对称共轭加成反应。结果表明,金属试剂参与的该类反应,大都能够得到比较好的收率和选择性。同时,配体的研究开发对于该类反应的结果有着较大程度的影响。     

NaHSO_4在有机合成中的新应用

近年来,硫酸氢钠(NaHSO4)作为一种稳定的、廉价的试剂,被广泛的应用在有机合成中。其可在不同的温和条件下高产率的催化氧化反应,C—O的形成与断裂等反应类型,根据硫酸氢钠的不同形式综述了其在有机合成中的其它新应用。     

Diastereoselective reductive amination reactions using novel metal–carbon catalysts prepared from inorganic Grignard reagents

A novel class of heterogeneous catalysts prepared from inorganic Grignard reagents is shown to provide finely divided transition metal–carbon nanostructures with potential advantages as selective hydrogenation catalysts under mild liquid‐phase conditions. Preliminary investigations of the catalytic behavior of these materials in diastereoselective reductive amination reactions are described. This revised version was published online in July 2006 with corrections to the Cover Date.     

Engineering selectivity into polymer-supported reagents for transition metal ion complex formation

Polymer-supported reagents are widely employed in the complexation of metal ions for applications in separations science, organic reactions (as catalysts) and in analytical chemistry (for processes requiring metal ion enrichment, detection and quantification). Various strategies for the continued development and optimization of polymer-supported reagents have evolved. This review cites ways in which polymer-supported reagents can be designed to achieve improved metal ion selectivities from the viewpoint of the mechanisms involved in the complexation of transition metal ions from aqueous solutions.     

2,2,6,6-四甲基哌啶-1-氧自由基在醇氧化研究中的应用

2,2,6,6-四甲基哌啶-1-氧自由基（TEMPO）作为有机小分子,形成的催化醇氧化反应体系相对传统醇氧化具有高效性、高选择性、反应条件温和等优点,可以解决传统醇氧化工艺中反应条件苛刻、成本高以及产生大量污染物的问题,是目前最具前景的醇氧化技术之一。本文综述了近年来关于TEMPO体系在催化醇氧化方面的相关研究进展,重点介绍了均相环境下过渡金属（铜、铁、钌等）参与和无过渡金属参与的TEMPO催化醇氧化,以及多相环境下的固载型TEMPO催化醇氧化,并根据催化反应效率、氧化成本、实际应用性等因素比较总结了均相催化和非均相催化两种类型催化氧化体系的优缺点。指出离子液体与TEMPO的耦合体系、廉价过渡金属掺杂的TEMPO体系和高稳定性碳基材料负载型TEMPO体系是该类型催化剂优化调控的目标与方向。