Review pubs.acs.org/CR
Transition-Metal-Free Coupling Reactions Chang-Liang Sun and Zhang-Jie Shi* Beijing National Laboratory of Molecular Sciences (BNLMS) and Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry and Green Chemistry Center, Peking University, 202 Chengfu Road, 098#, Beijing 100871, China State Key Laboratory of Organometallic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 200060, China 5.1.2. Hypervalent-Iodine-Mediated Oxidative Homocoupling for Carbon−Carbon Bond Formation 5.1.3. Hypervalent-Iodine-Mediated Oxidative Intramolecular Coupling for Carbon− Carbon Bond Formation 5.1.4. Hypervalent-Iodine-Mediated Oxidative Cross-Coupling for Carbon−Carbon Bond Formation 5.1.5. Hyperiodine-Mediated Oxidative C−N Bond Formation 5.2. DDQ-Promoted Oxidative Coupling Reactions 5.3. Brønsted-Acid-Catalyzed Oxidative Coupling Reactions 5.4. TEMPO-Mediated Oxidative Coupling Reactions 5.5. Other Types of Oxidative Coupling Reactions 5.6. Autoxidative Coupling of Heteroarenes 6. Photochemical Coupling Reactions 6.1. Visible-Light-Promoted Coupling Reactions Involving Organic Photoredox Catalysts 6.2. Photochemical Cross-Coupling Reactions via Aryl Cationic Intermediates 7. Transition-Metal-Free Coupling Reactions Involving Aryne Intermediates 8. Miscellaneous Transition-Metal-Free Coupling Reactions 8.1. Transition-Metal-Free Cross-Coupling Reactions of N-Tosylhydrazones as Versatile Reagents 8.2. Transition-Metal-Free Coupling of Carbon− Fluorine Bond 9. Conclusion and Outlook Author Information Corresponding Author Notes Biographies Acknowledgments References
CONTENTS 1. Introduction 2. Classification of Transition-Metal-Free Cross-Coupling Reactions 3. Base-Promoted HAS-Type Coupling Reactions 3.1. Homolytic Aromatic Substitution Reactions (HAS) 3.2. Base-Promoted Coupling Reactions of Aryl Halides with Arenes and Alkenes 3.2.1. Intermolecular Cross-Coupling of Aryl Halides with N-Containing Heteroarenes 3.2.2. Intermolecular Cross-Coupling of Aryl Halides with Common Arenes 3.2.3. Mechanistic Insight of the TransitionMetal-Free Cross-Coupling of Aryl Halides with Common Arenes 3.2.4. Intramolecular Cross-Coupling of Aryl Halides with Arenes 3.2.5. Intermolecular Cross-Coupling of Aryl Halides with Alkenes 3.2.6. Intramolecular Cross-Coupling of Aryl Halides with Alkenes 3.2.7. Alkoxycarbonylation of Aryl Halides 4. Transition-Metal-Free Cross-Coupling of Grignard Reagents 4.1. Cross-Coupling of Aryl Grignard Reagents with Aryl Halides through SRN1 Pathway 4.2. Coupling of Allylic Phosphorothioate Esters/ Halides with Grignard Reagents 4.3. Electrophilic Amination between Aryl Grignard Reagents and N-Chloroamines 4.4. Transition-Metal-Free Coupling of Organoboron Reagents with Alkenyl Grignard Reagents or Alkenyl Lithium Reagents 5. Transition-Metal-Free Oxidative Coupling Reactions 5.1. Hypervalent-Iodine-Mediated Oxidative Coupling Reactions 5.1.1. Hypervalent Iodine Reagents
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1. INTRODUCTION Transition-metal-catalyzed reactions have been studied since the very beginning of the past century and represent a great success in organic chemistry, along with the birth and growth of organometallic chemistry.1 Transition-metal-catalyzed coupling reactions, which were initiated in 1960s as a major topic in organometallic chemistry, have made significant progress in the last half century and become one of the most efficient and direct strategies for carbon−carbon bond formation.2 The extensive variations and modifications of transition-metalcatalyzed coupling reactions enabled wide applications in organic synthesis and were regarded as the most reliable, accurate, and powerful tools in chemists’ arsenal.3 Many named reactions have been assigned in the textbooks and are wellknown nowadays, together with the development of novel chemical reagents, such as organoboron4 and organotin reagents,5 and the renaissance of conventional organometallic reagents, including Grignard reagents,6 organolithium,7 organozinc,8 and organosilane reagents.9 Besides, the Mizoroki−Heck reaction is one perfect example for direct C−H functionalizations of olefins.10 Great successes and significance of transitionmetal-catalyzed coupling reactions were highlighted by the Nobel Prize in chemistry in 2010.11 Nevertheless, transition-metal-catalyzed coupling reactions are still limited in applications and confront challenges to some extent, owing to the instinctive drawbacks of the catalytic systems. First, most of the transition-metal catalysts are normally very expensive,12 and the supporting ligands are usually even more expensive and sometimes difficult to prepare. Second, most of the transition metals are toxic to different extents, and removal of trace amounts of transition-metal residues from desired products is quite costly and challenging, while crucial, especially in the pharmaceutical industry.13 Third, many transition-metal catalysts are usually sensitive to oxygen (O 2 ) and moisture; thus, very strict manipulation is indispensable. Fourth, in many cases, special additives and cocatalysts are also critical to promote the efficiency and selectivity of transformations.14 Last but not the least, the large consumption of transition metals does not indeed meet the requirement of sustainable development.15 Obviously, alternative pathways to construct C−C bonds under transitionmetal-free conditions to fulfill the classic transition-metalcatalyzed coupling reactions are highly appealing. Thus, studies on transition-metal-free coupling reactions are of great significance to provide a better understanding of how the reactions work with or without transition metals. Although much attention has been paid to the development of transition-metal-free coupling reactions and significant efforts have been made to promote such chemistry, actually the concept of transition-metal-free coupling reactions has not been well-defined by chemists. This phrase is often used to describe coupling reactions, which employ similar starting materials and give similar results with those catalyzed by transition-metal catalysts, while during the process no transition-metal catalysts were used. According to these facts, the scope of the so-called “transition-metal-free coupling reactions” seems quite broad, and investigations in this field lack specific criteria and systematic knowledge. On the other hand, the definition of the absence of transition-metal catalysts is still dubious due to the difficulty of rooting out transition-metal residues from starting materials, reagents, additives, as well as solvents. A trace amount of transition metals remaining in the reaction system
will fundamentally influence the exact reaction pathway in some cases, thus making it difficult to classify the corresponding reactions.16 Obviously, such observations are of great importance to explore the same chemistry in synthesis with an extremely low catalyst loading and to stimulate the thinking on the transition-metal-free processes. Therefore, in many cases, the “externally added transition-metal-free crosscoupling” might be a much better and more suitable definition to describe the “transition-metal-free coupling reactions”. However, in our mind, from the mechanistic point of view, transition-metal-free coupling reactions are proceeding in various pathways, and thus are distinct from the traditional transition-metal-catalyzed cross-couplings. All of the fundamental principles and elementary reactions in classic organometallic chemistry, presenting in common transition-metalcatalyzed coupling reactions, are not beneficial for the understanding of the present reaction process pathways any more. Thus, a reconsideration and summary of the transitionmetal-free coupling reactions mechanistically indeed makes great sense in an easy comprehension. In this Review, we classified the typical transition-metal-free coupling reactions and summarized their recent advances from different aspects.
2. CLASSIFICATION OF TRANSITION-METAL-FREE CROSS-COUPLING REACTIONS On the basis of the clarification of the concept on transitionmetal-free cross-coupling, we first summarize the reported cross-coupling reactions in the absence of transition-metal catalyst based on the proposed and proved catalytic pathways. Obviously, traditional substitution reactions, for example, the coupling between Grignard reagents and alkyl halides, are not included. On the basis of our opinion, typical transition-metalfree coupling reactions classified by the different pathways are summarized in Scheme 1: (1) radical pathway, mainly referring to homolytic aromatic substitution (HAS) type reactions; (2) radical cation pathway, especially hyperiodine-mediated oxidative coupling reactions; (3) cationic pathway, including DDQpromoted oxidative coupling reactions and photoinduced reactions via formation of triplet aryl cations; (4) electrophilic aromatic substitution (Friedel−Crafts reaction as the typical example); (5) nucleophilic aromatic substitution; (6) aryne pathway; and (7) classical organocatalysis pathway. Since Friedel−Crafts reactions have been widely studied for more than one century and have become a relative independent research field that was well-reviewed,17 it is not discussed any more in this Review. Similarly, the study on nucleophilic aromatic substitution reactions also owns its long history and colorful stories;18 therefore, only some relevant recent examples are included for a simple introduction and discussion. Although the classical “organocatalysis” can be formally included in such a category of transition-metal-free coupling reactions, they are more or less regarded as and deserve an independent research field, especially in comparison with “transition-metal catalysis”. The explosive growth of the investigations and interest has exhibited great significance in the application of organic synthesis. There are already numerous excellent summarizations and reviews19−21 on organocatalysis; therefore, no more discussion would be made in this Review. Furthermore, since “transition-metal-free” coupling reactions is entitled here, the reactions mediated or catalyzed by “main group elements” seem to be also included. However, alkali and alkaline earth metal compounds have been employed in many different types of reactions and play various roles. The compounds based on B
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produce a σ-complex, and the following elimination of the leaving group, normally hydrogen radical (Scheme 2). It should
Scheme 1. Typical Transition-Metal-Free Coupling Reactions through Various Pathways
Scheme 2. General Process of Homolytic Aromatic Substitution
also be pointed out that some HAS reactions involve an SET oxidation of radical σ-complex into cationic σ-complex, followed by rapid loss of a proton. Generally, the HAS reactions, in which aryl derivatives are used as the radical sources, have been regarded as one of the most important and straightforward synthetic methods to construct biaryl structural motifs.27 HAS reaction has a long history in modern organic chemistry, and various substrates can be used as the precursors of aryl radical, for instance, aroyl peroxides,28 aryl diazonium salts,29 and aryl halides.30 Considering the activating conditions and the accessibility of the starting materials, aryl halides (especially aryl bromides and aryl iodides) become the better choices for such HAS reactions. Further studies indicate that alkyl halides can also be subjected to similar conditions for alkyl−aryl couplings. The radical initiators for aryl halides in HAS reactions are commonly the combination of AIBN and organostannanes/organosilanes,31 as well as organoboron reagents,32 phosphite derivatives,33 and samarium diiodide34 in recent investigations. Although many earlier reviews, books, as well as some recent publications have summarized this important research field,35 a series of attractive novel discoveries on this aged chemistry bloomed in the past several years and deserve a new round of concern and discussion.
other p-block elements, such as indium,22 tin,23 germanium,24 bismuth,25 and so on, mainly reacted as organometallic reagents and also Lewis acids, showing very similarly characteristics with those of transition-metal-based Lewis acids, for example compounds of zinc, scandium, and titanium. Moreover, the chemistry of Lewis acids has been studied very extensively and regarded as a specific independent research field; therefore, no more discussion will be carried out in this Review. With this classification, the transition-metal-free coupling reactions that would be mainly introduced and discussed in this Review include (1) homolytic aromatic substitution (HAS) type radical reactions; (2) hyperiodine- and DDQ-promoted oxidative coupling reactions; (3) photochemical coupling reactions; (4) cross-coupling reactions via aryne intermediates; (5) coupling reactions of N-tosylhydrazones; and (6) some other special coupling reactions. Importantly, the comparison of the results between transition-metal-mediated and transition-metal-free coupling reactions will be discussed in most cases.
3.2. Base-Promoted Coupling Reactions of Aryl Halides with Arenes and Alkenes
3.2.1. Intermolecular Cross-Coupling of Aryl Halides with N-Containing Heteroarenes. In 2008, when Itami and co-workers tried to develop an iridium-catalyzed arylation of electron-deficient arenes,36 they unexpectedly found a coupling reaction of iodobenzene to pyrazine 1a, only promoted by stoichiometric amounts of KOtBu under microwave irradiation. Bromobenzene was less reactive than iodobenzene, and almost no reaction occurred when chlorobenzene or fluorobenzene was used (Table 1). Furthermore, this kind of transition-metalfree reaction could occur on aryl iodides and bromides with many electron-deficient nitrogen-containing heteroaromatic rings, such as pyridine (1b), pyridazine (1c), pyrimidine (1d), as well as quinoxaline (1e). The coupled products could be obtained in good yields, albeit with poor regioselectivity with respect to the heteroarenes (Table 2), which suggested a probably different reaction pathway with some reactions catalyzed by transition metals (normally with good regioselectivity of C−H bonds). Trace transition metals were contained in the system when all the used chemicals were examined by ICP-AES analysis. The
3. BASE-PROMOTED HAS-TYPE COUPLING REACTIONS 3.1. Homolytic Aromatic Substitution Reactions (HAS)
Homolytic aromatic substitution (HAS) is defined as the replacement of a leaving group Y on an aromatic ring by an attacking radical species.26 The whole reaction process generally involves the generation of an attacking radical species, addition of the new-formed radical species to aromatic ring to C
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Table 3. KOtBu-Promoted Coupling Reactions with Radical Scavengers
Table 1. Phenylation of Pyrazine 1a with Various Halobenzenes
entry
X
1 2 3 4
I Br Cl F
conditions 50 80 80 80
°C, °C, °C, °C,
yield (%)a
additive
yield
98 54
