Transition metal-catalyzed direct functionalization of C–H bonds is one of the key emerging strategies that is currently attracting tremendous attention with the aim to provide alternative environmentally friendly and efficient ways for the construction of C–C and C–hetero bonds. In particular, the strategy involving regioselective C–H activation assisted by various functional groups shows high potential, and significant achievements have been made in both the development of novel reactions and the mechanistic study. In this review, we attempt to give an overview of the development of utilizing the functionalities as directing groups. The discussion is directed towards the use of different functional groups as directing groups for the construction of C–C and C–hetero bonds via C–H activation using various transition metal catalysts. The synthetic applications and mechanistic features of these transformations will be discussed, and the review is organized on the basis of the type of directing groups and the type of bond being formed or the catalyst.

Transition metal-catalyzed C–H bond functionalizations by the use of diverse directing groups

The present review is devoted to summarizing the recent advances (2015-2017) in the field of metal-catalysed group-directed C-H functionalisation In order to clearly showcase the molecular diversity that can now be accessed by means of directed C-H functionalisation, the whole is organized following the directing groups installed on a substrate Its aim is to be a comprehensive reference work, where a specific directing group can be easily found, together with the transformations which have been carried out with it Hence, the primary format of this review is schemes accompanied with a concise explanatory text, in which the directing groups are ordered in sections according to their chemical structure The schemes feature typical substrates used, the products obtained as well as the required reaction conditions Importantly, each example is commented on with respect to the most important positive features and drawbacks, on aspects such as selectivity, substrate scope, reaction conditions, directing group removal, and greenness The targeted readership are both experts in the field of C-H functionalisation chemistry (to provide a comprehensive overview of the progress made in the last years) and, even more so, all organic chemists who want to introduce the C-H functionalisation way of thinking for a design of straightforward, efficient and step-economic synthetic routes towards molecules of interest to them Accordingly, this review should be of particular interest also for scientists from industrial R&D sector Hence, the overall goal of this review is to promote the application of C-H functionalisation reactions outside the research groups dedicated to method development and establishing it as a valuable reaction archetype in contemporary R&D, comparable to the role cross-coupling reactions play to date

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A comprehensive overview of directing groups applied in metal-catalysed C-H functionalisation chemistry.

Transition-metal-catalyzed cross-coupling reactions have been well-established as indispensable tools in modern organic synthesis. One of the major research goals in cross-coupling area is expanding the scope of the coupling partners. In the past decade, diazo compounds (or their precursors N-tosylhydrazones) have emerged as nucleophilic cross-coupling partners in C–C single bond or C═C double bond formations in transition-metal-catalyzed reactions. This type of coupling reaction involves the following general steps. First, the organometallic species is generated by various processes, including oxidative addition, transmetalation, cyclization, C–C bond cleavage, and C–H bond activation. Subsequently, the organometallic species reacts with the diazo substrate to generate metal carbene intermediate, which undergoes rapid migratory insertion to form a C–C bond. The new organometallic species generated from migratory insertion may undergo various transformations. This type of carbene-based coupling has proven...

Transition-Metal-Catalyzed Cross-Couplings through Carbene Migratory Insertion

The development of new methods for the direct functionalization of unactivated C–H bonds is ushering in a paradigm shift in the field of retrosynthetic analysis. In particular, the catalytic enantioselective functionalization of C–H bonds represents a highly atom- and step-economic approach toward the generation of structural complexity. However, as a result of their ubiquity and low reactivity, controlling both the chemo- and stereoselectivity of such processes constitutes a significant challenge. Herein we comprehensively review all asymmetric transition-metal-catalyzed methodologies that are believed to proceed via an inner-sphere-type mechanism, with an emphasis on the nature of stereochemistry generation. Our analysis serves to document the considerable and rapid progress within in the field, while also highlighting limitations of current methods.

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Catalytic Enantioselective Transformations Involving C-H Bond Cleavage by Transition-Metal Complexes.

During the past decades, synthetic organic chemistry discovered that directing group assisted C–H activation is a key tool for the expedient and siteselective construction of C–C bonds. Among the v...

Bidentate Directing Groups: An Efficient Tool in C-H Bond Functionalization Chemistry for the Expedient Construction of C-C Bonds.

Various rhodium-catalyzed double C–H activations are reviewed. These powerful strategies have been developed to construct C–C bonds, which might be widely embedded in complex aza-fused heterocycles, polycyclic skeletons and heterocyclic scaffolds. In particular, rhodium(III) catalysis shows good selectivity and reactivity to functionalize the C–H bond, generating reactive organometallic intermediates in most of the coupling reactions. Generally, intermolecular, intramolecular and multi-component coupling reactions via double C–H activations with or without heteroatom-assisted chelation are discussed in this review.

Rhodium-catalyzed C–C coupling reactions via double C–H activation

Rhodium(III)-Catalyzed Direct Selective C(5)–H Oxidative Annulations of 2-Substituted Imidazoles and Alkynes by Double C–H Activation

A special challenge in the field of asymmetric catalysis is the realization of remote stereocontrol. The problem can be extended to remote sites which must be activated to ensure better reactivity. While most early examples of remote asymmetric inductions rely on enzyme catalysis or intramolecular relay of chiral information through the substrate, current studies have demonstrated that chiral catalysts can facilitate enantioselectivity in variety of reactions. In particular, our group and the group of Jørgensen found that the well-established enamine chemistry of saturated carbonyl compounds could be expanded to polyconjugated 2,4-dienals based on the principle of vinylogy, thus leading to the remote e-site activation and still allowing highly stereoselective cycloadditions at b,e-sites of in situ formed linear trienamine intermediates. Moreover, such an activation mode was successfully applied to 2,4-dienone analogues. Unfortunately, it was not possible to utilize 2,4-dienones with an enolizable a’-alkyl substitution because the cross-conjugated trienamine species were preferably generated. In fact, we also found that the cyclic 2,4-dienone 1 would predominantly generate the cross-conjugated trienamine I, catalyzed by a primary amine, and then react with a dienophile by a a’,b-regioselective [4+2] annulation pathway (Scheme 1). To overcome the inherent preference for the formation of cross-conjugated trienamines from 2,4-dienones bearing an enolizable a’-alkyl group, we envisaged that an appropriately positioned d,e-C=C bond, as shown for the interrupted 3-allyl cyclohexen-2-one 2a (Scheme 1), would induce the generation of the desired polyconjugated linear trienamine II, rather than the dienamine III which has a higher energy. Thus, the electron-donating effects of the amine could be transmitted through the conjugated p system, and raise the HOMO energy of the remote d,e-C=C group to participate in asymmetric reactions. Based on the above considerations, we initially investigated the reaction of the 2,5-dienone 2 a and the 1-azadiene 3a, containing a 1,2-benzoisothiazole-1,1-dioxide moiety, in the presence of 9-amino-9-deoxyepiquinidine (C1) and benzoic acid (A1). To our gratification, the reaction proceeded smoothly in toluene at 35 8C, and the inverse-electrondemand aza-Diels–Alder cycloaddition product 4a was isolated in 63% yield with exclusive d,e-regioselectivity. More pleasingly, both diastereo(endo, > 19:1) and enantioselectivity (98% ee) are remarkable, even though the d,e-C= C bond is quite remote from chiral amine catalyst (Table 1, entry 1). It should be addressed that almost no reaction occurred for the reaction of the conjugated 2,4-dienone 1 and 3a under the same catalytic conditions, thus further verifying that the appropriately positioned d,e-C=C bond is crucial for inducing the formation of the required linear trienamine intermediate. 9-Amino-9-deoxyepiquinine (C2) afforded the product with the opposite configuration in excellent stereoselectivity (Table 1, entry 2), but C3, having with a free OH group, failed to catalyze the reaction (Table 1, entry 3). The acid additives had significant effects on the reaction. Salicylic acid (A2) produced better reactivity (Table 1, entry 4), and a slower reaction and even poor conversion was observed by using either A3 or A4 (Table 1, entries 5 and 6). Other solvents were tolerated though lower yields were obtained (Table 1, entries 7–10). Notably, the reaction still proceeded smoothly with a decreased amount (10 mol % or 5 mol %) of C1 in combination with A2, and better results were obtained after a longer reaction time (Table 1, entries 11 and 12). Consequently, a number of cyclic 2,5-dienones and electron-deficient 1-azadienes were investigated (Table 2). For the reactions of 2a, a variety of 3-vinyl-1,2-benzoisothiaScheme 1. Strategy for the formation of linear trienamine intermediate.

Trienamines Derived from Interrupted Cyclic 2,5‐Dienones: Remote δ,ε‐CC Bond Activation for Asymmetric Inverse‐Electron‐Demand Aza‐Diels–Alder Reaction

Switchable reaction patterns of β-substituted cyclic enones via amine-based dienamine activation are reported. While γ-regioselective vinylogous Michael addition was observed with alkylidenemalononitriles, a completely different [4 + 2] cycloaddition was obtained with allylidene- or alkynylidenemalononitrile substrates, affording densely substituted bicyclo[2.2.2]octanes or analogous architectures with moderate to excellent diastereo- and enantioselectivity by the catalysis of primary amines from natural quinidine or quinine. Importantly, high diastereodivergence was achieved through unusual hydrogen-bonding interactions of multifunctional primary-amine catalytic systems. Endo cycloadducts were efficiently produced using a combination of 9-amino-9-deoxyepiquinidine and salicylic acid, while exo variants were obtained using 6′-hydroxy-9-amino-9-deoxyepiquinidine. Moreover, we successfully isolated the Michael addition intermediates in some cases, indicating that the above [4 + 2] reaction via dienamine cat...

Lin Dong

Papers

Rhodium-catalyzed C–C coupling reactions via double C–H activation

Rhodium(III)-Catalyzed Direct Selective C(5)–H Oxidative Annulations of 2-Substituted Imidazoles and Alkynes by Double C–H Activation

Trienamines Derived from Interrupted Cyclic 2,5‐Dienones: Remote δ,ε‐CC Bond Activation for Asymmetric Inverse‐Electron‐Demand Aza‐Diels–Alder Reaction

Stereodivergence in amine-catalyzed regioselective [4 + 2] cycloadditions of β-substituted cyclic enones and polyconjugated malononitriles.

Rhodium‐Catalyzed Spirocyclic Sultam Synthesis by [3+2] Annulation with Cyclic N‐Sulfonyl Ketimines and Alkynes