Borylation Of Arenes Research Articles

Trialkoxysilane-Induced Iridium-Catalyzed para-Selective C–H Bond Borylation of Arenes

An ideal approach for the construction of aryl boron compounds is to selectively replace a C–H bond in arenes with a C–B bond, and controlling regioselectivity is one of the most challenging aspects of these transformations. Herein, we report an iridium-catalyzed trialkoxysilane protecting group-assisted regioselective C–H borylation of arenes, including derivatives of benzaldehydes, acetophenones, benzoic acids, benzyl alcohols, phenols, aryl silanes, benzyl silanes, and multi-functionalized aromatic rings are all well tolerated and gave the para -selective C–H borylation products in a short time without the requirement of inert gases atmosphere. The site-selective C–H borylation can be adjustable by installing the developed trialkoxysilane protecting group on different functional groups on one aromatic ring. Importantly, the preparation process of the trialkoxychlorosilane is efficient and scalable. Mechanistic and computational studies reveal that the steric hindrance of the trialkoxysilane protecting group plays a key role in dictating the para-selectivity.

Regioselective C(sp2)–H Borylation of (Hetero)Arenes under Cobalt Catalysis

Regioselective C(sp2)–H Borylation of (Hetero)Arenes under Cobalt Catalysis

Borenium‐Ions in Catalytic Aromatic C−H Borylation

AbstractThe catalytic C−H borylation of (hetero)arenes involving borenium species has witnessed fast development in the past decade. This review aims at summarize recent progress made in this field, with an emphasis on synthetic application and reaction mechanisms.

Ir-Catalyzed Ortho-Selective C-H Borylation of Difluoromethyl Arenes.

The difluoromethyl group (CF2H) has received great attention due to its distinct properties in recent years. Herein, we report a new strategy for postmodification of difluoromethyl compounds. Ortho-selective C-H borylation of difluoromethyl arenes is achieved by a cyclometalated mesoionic carbene-Ir complex. The regioselectivity is controlled by a hydrogen bond between CF2H and the boryl group via the outer-sphere direction.

Interrogating the Crucial Interactions at Play in the Chiral Cation-Directed Enantioselective Borylation of Arenes.

Rendering a common ligand scaffold anionic and then pairing it with a chiral cation represents an alternative strategy for developing enantioselective versions of challenging transformations, as has been recently demonstrated in the enantioselective borylation of arenes using a quinine-derived chiral cation. A significant barrier to the further generalization of this approach is the lack of understanding of the specific interactions involved between the cation, ligand, and substrate, given the complexity of the system. We have embarked on a detailed computational study probing the mechanism, the key noncovalent interactions involved, and potential origin of selectivity for the desymmetrizing borylation of two distinct classes of substrate. We describe a deconstructive, stepwise approach to tackling this complex challenge, which involves building up a detailed understanding of the pairwise components of the nominally three component system before combining together into the full 263-atom reactive complex. This approach has revealed substantial differences in the noncovalent interactions occurring at the stereodetermining transition state for C-H oxidative addition to iridium for the two substrate classes. Each substrate engages in a unique mixture of diverse interactions, a testament to the rich and privileged structure of the cinchona alkaloid-derived chiral cations. Throughout the study, experimental support is provided, and this culminates in the discovery that prochiral phosphine oxide substrates, lacking hydrogen bond donor functionality, can also give very encouraging levels of enantioselectivity, potentially through direct interactions with the chiral cation. We envisage that the findings in this study will spur further developments in using chiral cations as controllers in asymmetric transition-metal catalysis.

Facile Borylation of Alkenes, Alkynes, Imines, Arenes and Heteroarenes with N-Heterocyclic Carbene-Boranes and a Heterogeneous Semiconductor Photocatalyst.

Although the development of radical chain and photocatalytic borylation reactions using N-heterocyclic carbene (NHC)-borane as boron source is remarkable, the persistent problems, including the use of hazardous and high-energy radical initiators or the recyclability and photostability issues of soluble homogeneous photocatalysts, still leave great room for further development in a sustainable manner. Herein, we report a conceptually different approach toward highly functionalized organoborane synthesis by using recoverable ultrathin cadmium sulfide (CdS) nanosheets as a heterogeneous photocatalyst, and a general and mild borylation platform that enables regioselective borylation of a wide variety of alkenes (arylethenes, trifluoromethylalkenes, α,β-unsaturated carbonyl compounds and nitriles), alkynes, imines and electron-poor aromatic rings with NHC-borane as boryl radical precursor. Mechanistic studies and density functional theory (DFT) calculations reveal that both photogenerated electrons and holes on the CdS fully perform their own roles, thereby resulting in enhancement of photocatalytic activity and stability of CdS.

Facile Borylation of Alkenes, Alkynes, Imines, Arenes and Heteroarenes with N‐Heterocyclic Carbene‐Boranes and a Heterogeneous Semiconductor Photocatalyst

AbstractAlthough the development of radical chain and photocatalytic borylation reactions using N‐heterocyclic carbene (NHC)‐borane as boron source is remarkable, the persistent problems, including the use of hazardous and high‐energy radical initiators or the recyclability and photostability issues of soluble homogeneous photocatalysts, still leave great room for further development in a sustainable manner. Herein, we report a conceptually different approach toward highly functionalized organoborane synthesis by using recoverable ultrathin cadmium sulfide (CdS) nanosheets as a heterogeneous photocatalyst, and a general and mild borylation platform that enables regioselective borylation of a wide variety of alkenes (arylethenes, trifluoromethylalkenes, α,β‐unsaturated carbonyl compounds and nitriles), alkynes, imines and electron‐poor aromatic rings with NHC‐borane as boryl radical precursor. Mechanistic studies and density functional theory (DFT) calculations reveal that both photogenerated electrons and holes on the CdS fully perform their own roles, thereby resulting in enhancement of photocatalytic activity and stability of CdS.

Hybrid Machine Learning Approach to Predict the Site Selectivity of Iridium-Catalyzed Arene Borylation.

The borylation of aryl and heteroaryl C-H bonds is valuable for the site-selective functionalization of C-H bonds in complex molecules. Iridium catalysts ligated by bipyridine ligands catalyze the borylation of the C-H bond that is most acidic and least sterically hindered in an arene, but predicting the site of borylation in molecules containing multiple arenes is difficult. To address this challenge, we report a hybrid computational model that predicts the Site of Borylation (SoBo) in complex molecules. The SoBo model combines density functional theory, semiempirical quantum mechanics, cheminformatics, linear regression, and machine learning to predict site selectivity and to extrapolate these predictions to new chemical space. Experimental validation of SoBo showed that the model predicts the major site of borylation of pharmaceutical intermediates with higher accuracy than prior machine-learning models or human experts, demonstrating that SoBo will be useful to guide experiments for the borylation of specific C(sp2)-H bonds during pharmaceutical development.

Main Group Catalyzed Arene Borylation: Challenges and Opportunities.

Main Group Catalyzed Arene Borylation: Challenges and Opportunities.

Direct C(sp2)–H Borylation of Arenes Using Ir-bpy Porous Organic Polymers

Organoboron compounds are important building blocks in organic chemistry for a variety of key transformations in the production of compounds in the pharmaceutical and agricultural industries. Direct C–H borylation provides many advantages over more traditional transformation via halide groups that lead to stoichiometric waste. In the direct C(sp2)–H borylation of arenes, Ir-bipyridine systems have shown excellent performance. However, to make the formation of borylated products more benign and greener, transformations catalyzed by heterogeneous catalysts are appealing as they provide easier recovery and reuse of the catalyst. In this study, two different porous organic polymers (POPs) based on polystyrene-bearing bipyridine (bpy) ligands were synthesized. These POPs can, upon metal ligation in situ create an active catalyst that is capable of borylation twice per B2pin2 molecule. Our Ir systems were tested with different arenes, and a preliminary mechanistic investigation was performed. The system was recyclable for up to three consecutive recycles, albeit, the polymer backbone had indications of being borylated during the reaction.

Uncovering the Untapped Potential of the Use of Sodium Amides for Regioselective Arene Functionalisation.

Alkali-metal amides have become key reagents in synthetic chemistry, with special focus in deprotonation reactions. Despite the higher reactivity found in the heavier sodium and potassium amides, their insolubility and low stability has favoured the use of the more soluble lithium analogues, converting them into the most used non-nucleophilic bases. Studying the coordination effects of Lewis donor molecules such as tridentate amine PMDETA (N,N,N',N'',N''-pentamethyldiethylenetriamine) in combination with the sodium amide NaTMP (TMP = 2,2',6,6'-tetramethylpiperidide), we have been able to unlock the use of these reagents for the functionalisation of arenes, i.e. the deuterium incorporation by hydrogen isotope exchange and the deprotonative borylation of unactivated arenes. These findings show how sodium amides are not just a simple more sustainable replacement of their lithium counterparts, but also that they can display significantly enhanced reactivities allowing for the development of new transformations.

Progress in the Electrochemical Synthesis of Organoboron Compounds

AbstractOrganoboron is a class of compounds widely used in organic synthesis, pharmaceuticals, material science, sensors, and so on. Therefore, the development of efficient and selective electrochemical methods to synthesize organoboron has attracted much interest as an emerging sustainable technique of organic synthesis. Here, we summarized research on electrochemical borylations, including the electrochemically driven borylation of arenes, alkanes, aryl, or alkyl halides, activated carboxylic acids etc., based on direct electrolysis and metal‐free organocatalysis. We focus on the reaction mechanisms involved in single‐electron transfer and other radical processes. We believe that this review will inspire electrochemists to discover more efficient transformations to expand this field of borylation.

Photohemilabile PSP‐Rhodium Pincer Catalysts for Dehydrogenative C−H Bond Activation of Arenes

AbstractHemilabile ligands have been widely utilized for transition metal catalysis, but hemilability upon excitation, termed as “photohemilability”, is still elusive despite the recent progress of organometallic photocatalysis. In this study, it was discovered that Thioxantphos‐based PSP−Rh pincer complexes undergo dehydrogenative C−H bond activation of arenes under irradiation with visible light. Theoretical calculations indicate that a transient photodissociation of the strong S−Rh bond brought about by d‐d excitation on Rh is the key to realize oxidative addition of arenes to the Rh(I) center, which can be regarded as a photohemilabile behavior. This C−H bond activation process was successfully applied to visible light‐driven C−H borylation of simple arenes.

Understanding and Expanding Zinc Cation/Amine Frustrated Lewis Pair Catalyzed C-H Borylation.

[(NacNac)Zn(DMT)][B(C6F5)4], 1, (NacNac = {(2,6- i Pr2H3C6)N(CH3)C}2CH), DMT = N,N-dimethyl-4-toluidine), was synthesized via two routes starting from either (NacNac)ZnEt or (NacNac)ZnH. Complex 1 is an effective (pre)catalyst for the C-H borylation of (hetero)arenes using catecholborane (CatBH) with H2 the only byproduct. The scope included weakly activated substrates such as 2-bromothiophene and benzothiophene. Computational studies elucidated a plausible reaction mechanism that has an overall free energy span of 22.4 kcal/mol (for N-methylindole borylation), consistent with experimental observations. The calculated mechanism starting from 1 proceeds via the displacement of DMT by CatBH to form [(NacNac)Zn(CatBH)]+, D, in which CatBH binds via an oxygen to zinc which makes the boron center much more electrophilic based on the energy of the CatB-based LUMO. Combinations of D and DMT act as a frustrated Lewis pair (FLP) to effect C-H borylation in a stepwise process via an arenium cation that is deprotonated by DMT. Subsequent B-H/[H-DMT]+ dehydrocoupling and displacement from the coordination sphere of zinc of CatBAr by CatBH closes the cycle. The calculations also revealed a possible catalyst decomposition pathway involving hydride transfer from boron to zinc to form (NacNac)ZnH which reacts with CatBH to ultimately form Zn(0). In addition, the key rate-limiting transition states all involve the base, thus fine-tuning of the steric and electronic parameters of the base enabled a further minor enhancement in the C-H borylation activity of the system. Outlining the mechanism for all steps of this FLP-mediated process will facilitate the development of other main group FLP catalysts for C-H borylation and other transformations.

Sodium mediated deprotonative borylation of arenes using sterically demanding B(CH2SiMe3)3: unlocking polybasic behaviour and competing lateral borane sodiation.

The deprotonative metalation of organic molecules has become a convenient route to prepare functionalised aromatic substrates. Amongst the different metallating reagents available, sodium bases have recently emerged as a more sustainable and powerful alternative to their lithium analogues. Here we report the study of the sterically demanding electrophilic trap B(CH2SiMe3)3 for the deprotonative borylation of arenes using NaTMP (TMP = 2,2,6,6-tetramethylpiperidide) in combination with tridentate Lewis donor PMDETA (PMDETA = N,N,N',N'',N''-pentamethyldiethylenetriamine). Using anisole and benzene as model substrates, unexpected polybasic behaviour has been uncovered, which enables the formal borylation of two equivalents of the relevant arene. The combination of X-ray crystallographic and NMR monitoring studies with DFT calculations has revealed that while the first B-C bond forming process takes place via a sodiation/borylation sequence to furnish [(PMDETA)NaB(Ar)(CH2SiMe3)3] species, the second borylation step is facilitated by the formation of a borata-alkene intermediate, without the need of an external base. For non-activated benzene, it has also been found that under stoichimetric conditions the lateral sodiation of B(CH2SiMe3)3 becomes a competitive reaction pathway furnishing a novel borata-alkene complex. Showing a clear alkali-metal effect, the use of the sodium base is key to access this reactivity, while the metalation/borylation of the amine donor PMDETA is observed instead when LiTMP is used.

Phosphine-based metal-organic layers to construct single-site heterogeneous catalysts for arene borylation.

Metal-organic layers (MOLs) are versatile platforms for creating single-site heterogeneous catalysts. Incorporating molecular functionalities into MOLs is crucial for catalysis. In this study, we synthesized phosphine-containing MOLs constructed from Hf6-oxo secondary building units (SBUs) and phosphine ligands. The mono(phosphine)-Ir complexes generated by the metalation of TPP-MOL were highly active as heterogeneous catalysts for the C(sp2)-H borylation of a range of arenes. This research expands the diversity of MOL-based catalysts.

Borenium-Ion-Catalyzed C-H Borylation of Arenes.

Non-metal-catalyzed C-H borylation of arenes represents a sustainable and environment-friendly approach for the functionalization of arenes. Despite its promise as an alternative to traditional transition-metal systems, its substrate scope is generally limited to electron-rich arenes, thus hindering its application in organic synthesis. Herein, we report the development of a borenium-ion catalyst which can borylate unactivated arenes under ambient conditions with 4-chlorocatecholborane (HBcatCl) as borylation reagent. This metal-free catalytic system is suitable for the borylation of C-H bonds in sterically encumbered positions, which has been a challenging task for transition-metal systems. Additionally, this catalytic system allows para-selective one-pot borylation of phenols, which has not been achieved by using transition-metal systems. Our mechanistic investigations and computational studies support a synergistic activation of the H-BcatCl bond by the arene substrate and the borenium-ion catalyst. This generates a Wheland intermediate and a neutral hydroborane species and is followed by deprotonation of the Wheland intermediate with the hydroborane species. The latter step of C-H bond cleavage is likely the rate-limiting step.

Iridium‐Catalysed C−H Borylation of Fluoroarenes: Insights into the Balance between Steric and Electronic Control of Regioselectivity

AbstractThe iridium catalysed C−H borylation of polyfluorinated arenes and heteroarenes occurs rapidly and efficiently. As with other borylation reactions, whilst steric parameters dominate, an underlying electronic influence on reaction selectivity can be observed. Notably borylation regioselectivity in fluorinated (hetero)arenes is determined by purely electronic effects except for ortho‐borylation between two fluorine atoms where steric effects of fluorine substituents become apparent. Borylation at the para position with respect to fluorine is disfavoured whereas a strong electronic preference for borylation para to the azinyl nitrogen of pyridine is observed. When these features co‐operate high selectivity can be expected. For these reactions, computations based on transition state, rather than intermediate, energies in iridium geometries showed excellent agreement between predicted and observed selectivities.

Directed C–H borylation: From metal catalysis to metal free

<p indent="0mm">Organoborons play a highly important role in many science fields, range from synthetic chemistry to materials science to medicinal chemistry. The C−H borylation strategy has made significant development in recent decades, and its reaction system is changing from noble-metal catalysis to more environmentally friendly metal-free systems. Typically, an organic molecule contains multiple C−H bonds with subtle difference in activation barrier. Therefore, controlling the positional selectivity represents a key challenge in complex molecules. To override this intrinsic selectivity, introducing a directing group in molecules can exhibit different site-selectivity. This review focuses on the development of ortho-selective borylation of (hetero)arenes by various directing groups, including: (1) Metal-catalyzed directed C−H borylation; and (2) metal-free directed C−H borylation. The directed C−H borylation is shifting from noble metals to metal-free systems, breaking through the dependence of traditional means on metal catalysts and broadening the concept of C–H functionalization. In the first section, the development of transition metal catalysts for directed C−H<italic> </italic>borylation is summarized. Among various catalysts, the iridium complexes have proven to be most active toward C−H borylation. The 16e intermediate <sc>[Ir(dtbpy)(Bpin)₃] </sc>(dtbpy=4,4′-di-tert-butyl-2,2′-bipyridine, Bpin = 4,4,5,5-tetramethyl-1,3,2-dioxaborolane) has been proved to be the catalytically active species in the [Ir(X)(cod)]₂/dtbpy (X=OMe or Cl, cod=1,5-cyclooctadiene) catalyzed directed C−H borylation. Three different strategies have been developed for the direct regioselective C−H bond borylation: Chelate directed, relay directed, and outer-sphere directed. Notably, dimethylsilyl can be employed as the directing group in Ir-catalyzed ortho-borylation of arenes. In addition to iridium, the use of other transition metal catalysts including rhodium and palladium has met some success as well. The second section first analyses the disadvantages of traditional C−H<italic> </italic>borylation by transition metal catalysts. The requirement of precious metals and metal residues in the final product will limit the application of these processes, especially in large-scale synthesis. Alternatively, some novel metal-free electrophilic borylations of arenes have been reported which proceed via borenium or boronium species, but stoichiometric quantities of by-products are formed at the same time. Therefore, the development of simpler and efficient metal-free C−H bond borylation is highly desirable. Then we show our discovery on the development of a talent approach for the C−H bond borylation of (hetero)arenes including indoles, pyrroles and amides using the readily available BBr₃ without any additive. Other groups also reported some similar examples after our discovery. The concluding section of this review discusses the significance of the directed C−H<italic> </italic>borylation under metal-free conditions, and limitations of the known approaches in this field. The additional breakthroughs required to further advance the metal-free C−H functionalization are described in the concluding section of this review. We hope that this review will not only present the most exciting new discoveries for the C–H borylation of feedstock chemicals into valuable organoboron products, but also provide valuable guidance for researchers, especially in drug and natural product research, facilitating the continued development of synthetic chemistry.

Extended sulfonated bipyridine ligands targeting the para-selective borylation of arenes

Iridium-catalysed borylation of arenes is one of the most widely used metal-catalysed C–H activation processes to elaborate aromatic rings. Exercising catalyst control over regioselectivity of the C–H oxidative addition step remains an area of active research. In this paper we describe the synthesis of a selection of sulfonated bipyridine ligands in which there is an arene spacer between the sulfonate group and the bipyridine backbone. In comparison to our previous work which achieved meta-selective borylation and in which the sulfonated bipyridine bore no spacer, we hoped that these extended ligands may allow a larger macrocyclic transition state for C–H activation thus favouring the para-position. The synthesised ligands have been evaluated on a series of arenes bearing amides and quaternary ammonium salts at varying distances from the aromatic ring.