Carbon–carbon (C–C) bonds make up the skeletons of most organic molecules. The selective manipulation of C–C bonds offers a direct approach to editing molecular scaffolds but remains challenging. The ...kinetic inertness of C–C bonds can be overcome with transition-metal catalysis, which, nevertheless, relies on a substrate being highly strained or bearing a permanent directing group (DG). The driving force for C–C activation in these cases is strain relief and the formation of a stable metallocycle, respectively. Over the past two decades, a strategy has emerged that uses temporary or removable DGs to effect C–C activation of more common and less strained compounds. A variety of C–C bonds in less strained organic molecules are converted into more reactive transition-metal–carbon (M–C) bonds, enabling downstream transformations as part of diverse synthetic methods. This Review highlights catalytic approaches using temporary or removable DGs to help activate unstrained C–C bonds. The content is organized according to the temporary or removable nature of the DGs and includes applications in the synthesis of natural products or bioactive molecules.Selective manipulation of carbon–carbon bonds provides a direct approach to editing organic scaffolds. This Review describes the catalytic activation of unstrained carbon–carbon bonds enabled by temporary or removable directing groups.
A Pd and norbornene-catalyzed ortho-arene amination via Catellani-type C–H functionalization is reported. Aryl halides are used as substrates; N-benzoyloxyamines and isopropanol are employed as the ...amine source (oxidant) and reductant respectively. Examples are provided in 50–99% yields with high functional group tolerance. This method gives complementary site selectivity at the ortho- instead of ipso-position of aryl halides.
Conspectus Bridged and fused rings are commonly found in biologically important molecules. Current tactics to construct these ring systems are primarily based on stepwise ring formation (i.e., making ...one ring first followed by making another) and cycloaddition reactions (e.g., Diels–Alder reaction). To seek a complementary and perhaps more unified ring-forming approach, a deconstructive strategy based on C–C bond activation of cyclic ketones has been conceived. The named “cut-and-sew” reaction uses cyclic ketones with a tethered unsaturated moiety as substrates, which involves oxidative addition of a transition metal into the ketone C–C bond followed by intramolecular insertion of the unsaturated unit. This strategy has proved successful to access diverse ring scaffolds that are nontrivial to construct otherwise. This Account offers a concise summary of our laboratory’s systematic efforts in developing transition metal-catalyzed cut-and-sew reactions for the synthesis of bridged and fused rings over the past 10 years. In particular, we will focus on the reactions using readily available benzocyclobutenones and cyclobutanones. To date, the scope of the cut-and-sew reactions has been greatly expanded. First, diverse unsaturated moieties can serve as suitable coupling partners, such as alkenyl, alkynyl, allenyl, carbonyl, and iminyl groups. Second, a variety of reaction modes have been uncovered. In this account, (4 + 2), (4 + 2 – 1), and (4 + 1) cycloadditions that lead to a range of bridged or fused scaffolds will be summarized. Third, enantioselective transformations have been realized to efficiently construct chiral scaffolds, which are enabled by two strategies: enantio-determining migratory insertion and desymmetrization of cyclobutanones. Fourth, the synthetic applications have been demonstrated in streamlined total syntheses of a number of complex natural products. Compared to conventional synthetic logics, the cut-and-sew reaction allows the development of new bond-disconnecting strategies. Thus, the syntheses of (−)-cycloclavine, (−)-thebainone A, penicibilaenes, and the proposed cycloinumakiol are discussed in more detail. In addition to the narrative of the development of the cut-and-sew chemistry, this Account also aims to provide core guiding foundations and inspirations toward broader deconstructive synthetic applications through C–C bond cleavage. It is anticipated that more classes of cyclic compounds could serve as the substrates beyond benzocyclobutenones and cyclobutanones, and more diverse unsaturated moieties could be coupled. It can also be envisaged that more innovative utilization of this cut-and-sew strategy in complex organic syntheses will be revealed in the near future.
Herein we report a direct annulation between aryl iodides and epoxides through palladium/norbornene (Pd/NBE) cooperative catalysis. An iso‐propyl ester substituted NBE was found to be most efficient ...to suppress the formation of multiple‐NBE‐insertion byproducts and affords the desired 2,3‐dihydrobenzofuran derivatives in 44–99 % yields. The reaction is scalable and tolerates a range of functional groups. Asymmetric synthesis is realized using an enantiopure epoxide. Application of this method into a concise synthesis of insecticide fufenozide is demonstrated.
We go together: A simple and direct annulation between readily available aryl iodides and epoxides is enabled by palladium/norbornene (Pd/NBE) cooperative catalysis. This approach offers a practical synthesis of various 2,3‐dihydrobenzofuran derivatives.
On our path to the perfection of organic synthesis lies the challenge of controlling site selectivity, which is the differentiation of reactivity among the same kind of functional groups. Overcoming ...this challenge would significantly enhance synthetic efficiency and minimize waste production, which in turn calls for the development of new catalysts, reagents, tactics, and innovative strategies.
Alkylation reactions represent an important organic transformation to form C–C bonds. In addition to conventional approaches with alkyl halides or sulfonates as alkylating agents, the use of ...unactivated olefins for alkylations has become attractive from both cost and sustainability viewpoints. This Review summarizes transition-metal-catalyzed alkylations of various carbon–hydrogen bonds (addition of C–H bonds across olefins) using regular olefins or 1,3-dienes up to May 2016. According to the mode of activation, the Review is divided into two sections: alkylation via C–H activation and alkylation via olefin activation.
In the chemical industry, molecules of interest are based primarily on carbon skeletons. When synthesizing such molecules, the activation of carbon-carbon single bonds (C-C bonds) in simple ...substrates is strategically important: it offers a way of disconnecting such inert bonds, forming more active linkages (for example, between carbon and a transition metal) and eventually producing more versatile scaffolds. The challenge in achieving such activation is the kinetic inertness of C-C bonds and the relative weakness of newly formed carbon-metal bonds. The most common tactic starts with a three- or four-membered carbon-ring system, in which strain release provides a crucial thermodynamic driving force. However, broadly useful methods that are based on catalytic activation of unstrained C-C bonds have proven elusive, because the cleavage process is much less energetically favourable. Here we report a general approach to the catalytic activation of C-C bonds in simple cyclopentanones and some cyclohexanones. The key to our success is the combination of a rhodium pre-catalyst, an N-heterocyclic carbene ligand and an amino-pyridine co-catalyst. When an aryl group is present in the C3 position of cyclopentanone, the less strained C-C bond can be activated; this is followed by activation of a carbon-hydrogen bond in the aryl group, leading to efficient synthesis of functionalized α-tetralones-a common structural motif and versatile building block in organic synthesis. Furthermore, this method can substantially enhance the efficiency of the enantioselective synthesis of some natural products of terpenoids. Density functional theory calculations reveal a mechanism involving an intriguing rhodium-bridged bicyclic intermediate.
Herein we describe a rhodium-catalyzed (4+1) cyclization between cyclobutanones and allenes, which provides a distinct 4.2.1-bicyclic skeleton containing two quaternary carbon centers. The reaction ...involves C–C activation of cyclobutanones and employs allenes as a one-carbon unit. A variety of functional groups can be tolerated, and a diverse range of polycyclic scaffolds can be accessed. Excellent enantioselectivity can be obtained, which is enabled by a TADDOL-derived phosphoramidite ligand. The bridged bicyclic products can be further functionalized or derivatized though simple transformations.
A direct catalytic method is described for the α,β-desaturation of N-protected lactams to their conjugated unsaturated counterparts under mildly acidic conditions. The reaction is consistently ...operated at room temperature and tolerates a wide range of functional groups, showing reactivity complementary to that of prior desaturation methods. Lactams with various ring sizes and substituents at different positions all reacted smoothly. The synthetic utility of this method is demonstrated in a concise synthesis of Rolipram. In addition, linear amides also prove to be competent substrates, and the phthaloyl-protected product serves as a convenient precursor to access various conjugated carboxylic acid derivatives. Strong bases are avoided in this desaturation approach, and the key is to merge soft enolization with a Pd-catalyzed oxidation process.
While metathesis reactions involving carbon–carbon double bonds, namely olefin metathesis, have been well established with broad utility in organic synthesis and materials science, direct metathesis ...of kinetically less accessible C–C single bonds is extremely rare. Here we report a ruthenium-catalysed reversible C–C single-bond metathesis reaction that allows redox- and pH-neutral biaryl synthesis. Assisted by directing groups, unstrained homo-biaryl compounds undergo aryl exchanges to generate cross-biaryl products, catalysed by a well-defined air-stable ruthenium(II) complex. Functional groups reactive under typical cross-coupling reactions, such as halogen, silyl and boronate moieties, are compatible under the metathesis conditions. Mechanistic studies disclose an intriguing ‘olefin-metathesis-like’ pathway that involves an unexpected heptacoordinated, 18-electron closed-shell intermediate. The distinct reaction mode discovered here is expected to inspire the development of more general C–C single-bond metathesis and orthogonal cross-coupling reactions.Metathesis reactions involving carbon–carbon double bonds have been well established, but direct metathesis of carbon–carbon single bonds is extremely rare. Now, a ruthenium-catalysed carbon–carbon single-bond metathesis reaction has been developed with unstrained homo-biaryl substrates. The reaction shows wide functional group tolerance and operates via an ‘olefin-metathesis-like’ mechanism.
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