Palladium-Catalyzed Regioselective B(3,5)-Dialkenylation and B(4)-Alkenylation of o-Carboranes.

Picolyl group directed B(3,5)-dialkenylation and B(4)-monoalkenylation of o-carboranes has been developed with a very low palladium catalyst loading. The degree of substitution is determined by the cage C(2)-substituents due to steric reasons. On the basis of experimental results, a plausible mechanism is proposed including electrophilic palladation and alkyne insertion followed by protonation.

Functionalization of o-carboranes via carboryne intermediates.

Carborynes (1,2-dehydro-o-carborane and 1,3-dehydro-o-carborane), three-dimensional analogues of benzyne, can be generated in situ from the precursors 1-X-2-Li-1,2-C2B10H10 (X = Br, I, OTs, OTf), or 1-Me3Si-2-[IPh(OAc)]-1,2-C2B10H10 or [1-Li-3-N2-1,2-C2B10H10][BF4]. They are a class of very useful synthons for the synthesis of a large variety of functionalized carborane derivatives for potential application in medicine, materials science and organometallic/coordination chemistry. The experimental data demonstrate that there is a correspondence between the reactions of carborynes and those of benzyne with alkenes, dienes, alkynes, aromatics or heteroaromatics in a pericyclic reaction fashion. On the other hand, carborynes have unique properties of their own owing to their steric/electronic features. They undergo regioselective sp2/sp3 C-H bond and N-Li bond insertion reactions, which has not been observed for benzyne. This review provides a comprehensive overview of recent advances in this interesting research field with considerable attention devoted to the reaction modes and the mechanisms involved.

A Strategy for Selective Catalytic B-H Functionalization of o-Carboranes.

Carboranes are a class of polyhedral carbon-boron molecular clusters featuring three-dimensional aromaticity, which are often considered as 3D analogues of benzene. Their unique structural and electronic properties make them invaluable building blocks for applications ranging from functional materials to versatile ligands to pharmaceuticals. Thus, selective functionalization of carboranes has received tremendous research interest. In earlier days, the vast majority of the works in this area were focused on cage carbon functionalization via facile deprotonation of cage CH, followed by reaction with electrophiles. On the contrary, cage B-H activation is very challenging since the 10 B-H bonds on o-carborane are very similar, and how to achieve the desired transformation at specific boron vertex is a long-standing issue.As carbon is considered more electronegative than boron, this property results in different vertex charges on the o-carborane cage, which follow the order B(3,6)-H ≪ B(4,5,7,11)-H < B(8,10)-H < B(9,12)-H. We thought that this difference may trigger the favorite interaction of a proper transition metal complex with a specific B-H bond of carborane, which could be utilized to solve the selectivity issue. Accordingly, our strategy is described as follows: (1) electron-rich transition metal catalysts are good for the activation of the most electron-deficient B(3,6)-H bonds (connected to both cage C-H vertices); (2) electron-deficient transition metal catalysts are good for the activation of the relatively electron-rich B(8,9,10,12)-H bonds (with no bonding to either cage C-H vertices); and (3) directing-group-assisted transition metal catalysis is appropriate for the activation of the B(4,5,7,11)-H bonds (connected to only one cage C-H vertex), whose vertex charges lie in the middle of the range for the 10 B-H bonds. This strategy has been successfully applied by our laboratory and other groups in the development of a series of synthetic routes for catalytic selective activation of B-H bonds of the carborane cage, resulting in the synthesis of a large number of cage-boron-functionalized carborane derivatives in a regioselective and catalytic fashion. Subsequently, significant progress in this emerging area has been made.In 2013 we reported the selective tetrafluorination of o-carboranes at the B(8,9,10,12)-H bonds using an electron-deficient Pd(II) salt, [Pd(MeCN)4][BF4], as the catalyst. In 2014 we disclosed the first example of carboxy-directed alkenylation of o-carboranes at the B(4) vertex promoted by an Ir(III) catalyst. Subsequently, in 2017 we presented an electron-rich Ir(I)-catalyzed diborylation of o-carboranes at the B(3,6)-H bonds. We also uncovered the first example of Pd-catalyzed asymmetric synthesis of chiral-at-cage o-carboranes in 2018. These proof-of-principle studies have greatly stimulated research activities in selective B-H activation of carboranes and boron clusters enabled by transition metal catalysts. We have so far developed a toolbox of synthetic methods for selective catalytic cage B-olefination, -arylation, -alkenylation, -alkynylation, -oxygenation, -sulfenylation, -borylation, -halogenation, and -amination. We have recently expanded our research to base metal catalysis. As the field progresses, we expect that other methods for regioselective cage B-H activation will be invented, and the results detailed in this Account will promote these efforts.

Iridium-Catalyzed Regioselective B(3)-Alkenylation/B(3,6)-Dialkenylation of o-Carboranes by Direct B-H Activation.

Invited for the cover of this issue is the group of Zaozao Qiu and Zuowei Xie at the Shanghai Institute of Organic Chemistry, CAS. The image depicts the cis- and trans-o-carborane products reported in this work. Read the full text of the article at 10.1002/chem.202000549.

Iridium-Catalyzed Regioselective B(3)-Alkenylation/B(3,6)-Dialkenylation of o-Carboranes by Direct B-H Activation.

Iridium-catalyzed formal alkyne hydroboration with cage B-H of o-carborane has been achieved, leading to the controlled synthesis of a series of 3,6-[trans-(AlkCH=CH)]2 -o-carboranes (Alk=alkyl), 3-cis-(ArCH=CH)-o-carboranes (Ar=aryl), and 3-cis-(ArCH=CH)-6-trans-(AlkCH=CH)-o-carboranes in high yields with excellent regio- and very good cis-trans selectivity. The most electron-deficient B(3,6)-H vertices favor oxidative addition on electron-rich metal centers, which is responsible for the regioselectivity. On the other hand, the configuration of the resultant olefinic units is dominated by alkyne substituents. Alkyl groups lead to a trans-configuration whereas bulky aryl substitutions result in cis-configuration.

Pd-Catalyzed Selective Bifunctionalization of 3-Iodo-o-Carborane by Pd Migration.

A palladium-catalyzed highly selective 3,4-bifunctionalization of 3-I-o-carborane has been developed, leading to the preparation of 3-alkenyl-4-R-o-carboranes (R=alkyl, alkynyl, aryl, allyl, CN, and amido) in high to excellent yields. This protocol combines the sequential activation of cage B(3)-I and B(4)-H bonds by Pd migration from exo-alkenyl sp2 C to cage B(4), which is driven by thermodynamic force. This represents a brand-new strategy for selective bifunctionalization of carboranes with two different substituents.

Enantioselective Synthesis of Chiral-at-Cage o-Carboranes via Pd-Catalyzed Asymmetric B-H Substitution.

Carborane cage chirality is an outstanding issue of great interest as the icosahedral carboranes have wide applications in medicinal and materials chemistry. The synthesis of optically active carborane derivatives, whose chirality is associated with the substitution patterns on the polyhedron, will open new avenues to carborane chemistry. We report herein an efficient method to achieve chiral-at-cage arylation of o-carboranes with high regio- and enantioselectivities by a strategy of palladium-catalyzed asymmetric intramolecular B-H arylation and cyclization. This represents the first example of the enantioselective reaction on carboranes, providing an efficient way for the construction of chiral-at-cage compounds with new skeletons.

Transition-Metal-Catalyzed Selective Cage B-H Functionalization of o-Carboranes.

Carboranes are a class of carbon-boron molecular clusters with unusual thermal and chemical stabilities. They have been proved as very useful building blocks in supramolecular design, optoelectronics, nanomaterials, boron neutron capture therapy agents and organometallic/coordination chemistry. Thus, the functionalization of o-carboranes has received growing interests. Over the past decades, most of the works in this area have been focused on cage carbon functionalization as the weakly acidic cage C-H proton can be readily deprotonated by strong bases. In sharp contrast, selective cage B-H activation/functionalization among chemically very similar ten B-H vertices is very challenging. Considering the differences in electron density of ten cage B-H bonds in o-carborane and the nature of transition metal complexes, we have tackled this selectivity issue by means of organometallic chemistry. Our strategy is as follows: using electron-rich transition metal catalysts for the functionalization of the most electron-deficient B(3,6)-H vertices (bonded to both cage CH vertices); using electron-deficient transition-metal catalysts for the functionalization of relatively electron-rich B(8,9,10,12)-H vertices (with no bonding to both cage CH vertices); and using the combination of directing groups and electrophilic transition metal catalysts for the functionalization of B(4,5,7,11)-H vertices (bonded to only one cage CH vertex). Successful applications of such a strategy result in the preparation of a large variety of cage B-functionalized carboranes in a regioselective and catalytic manner, which are inaccessible by other means. It is believed that as this field progresses, other cage B-functionalized carboranes are expected to be synthesized, and the results detailed in this concept article will further these efforts.

Photoarylation of Iodocarboranes with Unactivated (Hetero)Arenes: Facile Synthesis of 1,2-[(Hetero)Aryl]n -o-Carboranes (n=1,2) and o-Carborane-Fused Cyclics.

Photoarylation of iodocarboranes with unactivated arenes/heteroarenes at room temperature has been achieved, for the first time, thus leading to the facile synthesis of a large variety of cage carbon mono(hetero)arylated and di(hetero)arylated o-carboranes. This work represents a clean, efficient, transition-metal-free, and cheap synthesis of functionalized carboranes, which has significant advantages over the known methods.

Facile Synthesis of N-Carboranyl Amines through an ortho-Carboryne Intermediate.

The efficient o-carboryne precursor 1-Li-2-OTf-o-C2 B10 H10 reacts with lithium amides at room temperature to give a series of N-carboranyl amines in moderate to high isolated yields. This reaction is compatible with a broad substrate scope from primary to secondary, alkyl to aryl amines. The reaction mechanism is also proposed on the basis of experimental results and DFT calculations. This represents the first general and efficient method for the synthesis of 1-NR(1) R(2) -o-carboranes.

Transition-metal-mediated three-component cascade cyclization: selective cage B-C(sp2) coupling of carborane with aromatics and synthesis of carborane-fused tricyclics.

Zirconium/nickel comediated one-pot three-component cascade cyclization of carboryne, alkene, and 2-bromophenyltrimethylsilylacetylene has been achieved, leading to the formation of a series of C,C,B-substituted carborane-fused tricyclics. On the basis of experimental results, a plausible mechanism is proposed including [2 + 2 + 1] cross-cyclotrimerization followed by intramolecular direct selective cage B-C(sp(2)) coupling. This represents the first example of direct cage B-C(phenyl) coupling via cage B-H activation.

Palladium-catalyzed selective fluorination of o-carboranes.

A Pd(II)-catalyzed direct selective fluorination reaction of carboranes using a F(+) reagent has been developed, leading to a series of polyfluorocarboranes in high isolated yields. The mechanism involving electrophilic B-H activation, oxidation of Pd(II) by F(+) species, and reductive elimination is proposed.

Iridium-catalyzed regioselective B(3,6)-dialkenylation or B(4)-alkenylation of o-carboranes via B-H activation and 1,2-carbon migration of alkynes.

An efficient Ir-catalyzed cage boron alkenylation of 1-(2'-picolyl)-o-carboranes with diarylacetylenes has been developed, leading to a wide variety of B-H geminal addition products via 1,2-carbon migration of alkynes. The steric effect of cage carbon substituents has a great impact on the regioselectivity of such alkenylation reactions.

Reaction of 4-Bpin-o-Carborane with Ketones: Sequential Carbon Vertex Alkylation and B-B Bond Activation.

Diboron compounds are important reagents in a series of transition metal catalyzed or metal-free borylation reactions. We describe herein a unique reactivity of 4-Bpin-o-carborane with ketones under basic conditions, leading to sequential cage carbon alkylation, B-B bond activation and unexpected O-migration. The reaction was compatible with a good substrate scope including dialkyl or alkyl aryl ketones. The reaction mechanism is also proposed, involving cage CH deprotonation, nucleophilic attack of ketone, and O-migration along with B-B bond cleavage.

Transition-metal-promoted or -catalyzed exocyclic alkyne insertion via zirconacyclopentene with carborane auxiliary: formation of symmetric or unsymmetric benzocarboranes.

Reactions of Cp(2)Zr(µ-Cl)(µ-C(2)B(10)H(10))Li(OEt(2))(2) with alkynes R(1)C≡CR(2) gave as insertion products zirconacyclopentenes incorporating a carboranyl unit, 1,2-[Cp(2)ZrC(R(1))═C(R(2))]-1,2-C(2)B(10)H(10) (1). Treatment of 1 with another type of alkyne R(3)C≡CR(4) in the presence of stoichiometric amounts of NiCl(2) and FeCl(3) or a catalytic amount of NiCl(2) afforded symmetric or unsymmetric benzocarboranes. The regioselectivity was dominated by the polarity of the corresponding alkynes. These reactions could also be carried out in one pot, leading to the equivalent of a three-component [2 + 2 + 2] cycloaddition of carboryne and two different alkynes promoted by transition metals. A reaction mechanism was proposed after the isolation and structural characterization of the key intermediate nickelacycle. These results show that nickel complexes are more reactive than the iron ones toward the insertion of alkynes but that the latter do not initiate the trimerization of alkynes, making the insertion of activated alkynes possible. This work also demonstrates that a catalytic amount of nickel works as well as a stoichiometric amount of nickel in the presence of excess FeCl(3) for the reactions. Such a catalytic reaction may shed some light on the development of zirconocene-based catalytic reactions.

Transition metal-carboryne complexes: synthesis, bonding, and reactivity.

The construction and transformation of metal-carbon (M-C) bonds constitute the central themes of organometallic chemistry. Most of the work in this field has focused on traditional M-C bonds involving tetravalent carbon: relatively little attention has been paid to the chemistry of nontraditional metal-carbon (M-C(cage)) bonds, such as carborane cages, in which the carbon is hypervalent. We therefore initiated a research program to study the chemistry of these nontraditional M-C(cage) bonds, with a view toward developing synthetic methodologies for functional carborane derivatives. In this Account, we describe our results in constructing and elucidating the chemistry of transition metal-carboryne complexes. Our work has shown that the M-C(cage) bonds in transition metal-carboranyl complexes are generally inert toward electrophiles, and hence significantly different from traditional M-C bonds. This lack of reactivity can be ascribed to steric effects resulting from the carboranyl moiety. To overcome this steric problem and to activate the nontraditional M-C(cage) bonds, we prepared a series of group 4 and group 10 transition metal-carboryne complexes (where carboryne is 1,2-dehydro-o-carborane), because the formation of metallacyclopropane opens up the coordination sphere and creates ring strain, facilitating the reactions of M-C(cage) bonds with electrophiles. Structural and theoretical studies on metal-carboryne complexes suggest that the bonding interaction between the metal atom and the carboryne unit is best described as a resonance hybrid of the M-C σ and M-C π bonds, similar to that observed in metal-benzyne complexes. The nickel-carboryne complex (η(2)-C(2)B(10)H(10))Ni(PPh(3))(2) can (i) undergo regioselective [2 + 2 + 2] cycloaddition reactions with 2 equiv of alkyne to afford benzocarboranes, (ii) react with 1 equiv of alkene to generate alkenylcarborane coupling products, and (iii) also undergo a three-component [2 + 2 + 2] cyclotrimerization with 1 equiv of activated alkene and 1 equiv of alkyne to give dihydrobenzocarboranes. The reaction of carboryne with alkynes is also catalyzed by Ni species. Subsequently, a Pd/Ni co-catalyzed [2 + 2 + 2] cycloaddition reaction of 1,3-dehydro-o-carborane with 2 equiv of alkyne was developed, leading to the efficient formation of C,B-substituted benzocarboranes in a single process. In contrast, the zirconium-carboryne species, generated in situ from Cp(2)Zr(µ-Cl)(µ-C(2)B(10)H(10))Li(OEt(2))(2), reacts with only 1 equiv of alkyne or polar unsaturated organic substrates (such as carbodiimides, nitriles, and azides) to give monoinsertion metallacycles, even in the presence of excess substrates. The resultant five-membered zirconacyclopentenes, incorporating a carboranyl unit, are an important class of intermediates for the synthesis of a variety of functionalized carboranes. Transmetalation of zirconacyclopentenes with other metals, such as Ni and Cu, was also found to be a very useful tool for various chemical transformations. Studies of metal-carboryne complexes remain a relatively young research area, particularly in comparison to the rich literature of metal-benzyne complexes. Other transition metal-carborynes are expected to be prepared and structurally characterized as the field progresses, and the results detailed here will further that effort by providing easy access to a wide range of functionalized carborane derivatives.

Regioselective insertion of carborynes into ethereal C-H bond: facile synthesis of α-carboranylated ethers.

Carborynes can exist in two resonance forms, bonding form vs biradical form. The biradical form can be readily generated via the elimination of LiI from 1-iodo-n-lithio-1,n-C(2)B(10)H(10) (n = 2, 7) under UV irradiation. They can undergo α-C-H bond insertion with aliphatic ethers, affording α-carboranylated ethers in excellent regioselectivity at room temperature. This serves as a new methodology for the generation of a series of functionalized carboranes bearing alkoxy units.

Pd-Catalyzed sequential B(3)-I/B(4)-H bond activation for the synthesis of 3,4-benzo-o-carboranes.

A palladium-catalyzed sequential B(3)-I and B(4)-H bond activation has been achieved for the synthesis of 3,4-benzo-o-carboranes via a formal [2 + 2 + 2] cycloaddition of 3-I-o-carborane with 2 equiv. of arylalkynes. This represents a new protocol to construct o-carborane-fused cyclics in one process, in which the Pd fragment migrates formally from the B(3) to B(4) position of the cage.

Pd-catalyzed selective tetrafunctionalization of diiodo-o-carboranes.

A palladium-catalyzed highly selective tetrafunctionalization of 3,6-I2-o-carborane and 4,7-I2-o-carborane has been developed, leading to the preparation of 3,6-dialkenyl-4,11-R2-o-carboranes and 4,7-dialkenyl-5,11-R2-o-carboranes (R = alkyl, allyl and aryl) in moderate to excellent yields. This represents a new strategy for selective synthesis of polyfunctionalized o-carborane derivatives via a one-pot process.

Ir-catalyzed enantioselective B-H alkenylation for asymmetric synthesis of chiral-at-cage o­carboranes.

The asymmetric synthesis of chiral-at-cage o-carboranes, whose chirality is associated with the substitution patterns on the polyhedron, is of great interest as the icosahedral carboranes have wide applications in medicinal and materials chemistry. Herein we report an intermolecular Ir-catalyzed enantioselective B-H alkenylation for efficient and facile synthesis of chiral-at-cage o-carboranes with new skeletons under mild reaction conditions. Generally very good to excellent yields with up to 99% ee can be achieved in this Ir-catalyzed B-H alkenylation. The enantiocontrol model is proposed based on Density Functional Theory calculations in which the use of chiral phosphoramidite ligand is essential for such asymmetric o-carborane B-H alkenylation.