Acyl‐Directed ortho‐Borylation of Anilines and C7 Borylation of Indoles using just BBr3

Indoles are privileged heterocycles found in many biologically active pharmaceuticals and natural products. However, the selective functionalization of the benzenoid moiety in indoles in preference to the more reactive pyrrolic unit is a significant challenge. Herein we report that N‐acyl directing groups enable the C7‐selective C?H borylation of indoles using just BBr₃. This transformation shows some functional‐group tolerance and notably proceeds with C6 substituted indoles. The directing group can be readily removed in situ and the products isolated as the pinacol boronate esters. Acyl‐directed electrophilic borylation can be extended to carbazoles and anilines with excellent ortho selectivity. 4‐amino‐indoles are amenable to this process, with acyl group installation and directed electrophilic C?H borylation enabling selective formation of C5‐BPin‐indoles.     

Vinylic C?H Borylation of Cyclic Vinyl Ethers with Bis(pinacolato)diboron Catalyzed by an Iridium(I)‐dtbpy Complex

Borylation of the vinylic C? H bond of 1,4‐dioxene, 2,3‐dihydrofuran, 3,4‐dihydro‐2H‐pyran and their γ‐substituted analogs was carried out in the presence of bis(pinacolato)diboron (B₂pin₂) and a catalytic amount of Ir^I‐dtbpy (dtbpy=4,4′‐di‐tert‐butyl‐2,2′‐bipyridine) complex. The two boron atoms in B₂pin₂ participated in the coupling, thus giving two equivalents of the coupling product from one equivalent of B₂pin₂. The borylation of 1,4‐dioxene in hexane resulted in 81 % yield at room temperature. The borylation of 2,3‐dihydrofurans at 80 °C in octane suffered from low regioselectivity, and gave a mixture of α‐ and β‐coupling products even for hindered γ‐disubstituted analogs, but γ‐substituted analogs of 3,4‐dihydro‐2H‐pyran achieved high α‐selectivity, giving single coupling products. This protocol was applied to the syntheses of a key precursor of vineomycinone B2 methyl ester and other C‐substituted D ‐glucals by borylation of protected D ‐glucals with B₂pin₂ to give α‐boryl glucal followed by cross‐coupling with haloarenes, benzyl bromide, and allyl bromide. A catalytic cycle that involves the oxidative addition of sp² C? H bond to iridium(III)‐trisboryl intermediate as the rate‐determining step has been proposed.     

Iridium Diphosphine Complexes Featuring Pendant Lewis Acids: Efforts toward Selective Heteroarene Borylation

The selective forging of carbon-boron bonds via C−H borylation stands as a central means to access fine chemical precursors. Notwithstanding, achieving selectivity in this reaction is difficult, calling for the design of molecular catalysts that offer a vector for mechanistic control. This report aims to achieve such through the strategic placement of Lewis acids in the ligand periphery, permitting engagement with a substrate through non-covalent Lewis acid/base interactions. Various diphosphine iridium(I/III) complexes having 1,2-bis(di-n-propylphosphino)ethane) (dnppe), tetrakisallylphosphinoethane (tape) and 1,2-bis(di(3-dicyclohexylboranyl)propylphosphino)ethane (P₂B^Cy₄) ligands were prepared. The P₂B^Cy₄ ligand scaffold boasts four Lewis acidic boron groups in its secondary coordination sphere, which are shown to engage with N-heterocycles, tape is the precursor to P₂B^Cy₄, and dnppe is a saturated n-propyl analogue devoid of boron functionality. Select combinations of such iridium salts/diphosphine ligands were assayed in the catalytic borylation of 2-methylpyridine using B₂Pin₂ (Pin=pinacol).     

Sequential C−H Borylation and N‐Demethylation of 1,1′‐Biphenylamines: Alternative Route to Polycyclic BN‐Heteroarenes

Described herein is an unprecedented access to BN‐polyaromatic compounds from 1,1′‐biphenylamines by sequential borane‐mediated C(sp²)?H borylation and intramolecular N‐demethylation. The conveniently in situ generated Piers’ borane from a borinic acid reacts with a series of N,N‐dimethyl‐1,1′‐biphenyl‐2‐amines in the presence of PhSiH₃ to afford six‐membered amine‐borane adducts bearing a C(sp²)?B bond at the C2′‐position. These species undergo an intramolecular N‐demethylation with a B(C₆F₅)₃ catalyst to provide BN‐isosteres of polyaromatics. According to computational studies, a stepwise ionic pathway is suggested. Photophysical characters of the resultant BN‐heteroarenes shown them to be distinctive from those of all‐carbon analogues.     

C?H Functionalizations by Means of Direct Borane–Hydrocarbon Dehydrogenations and Dehydrocarbonations

The C? H functionalization of methane by means of direct C? H borations with BH₃ or MeBH₂ is compared computationally (using the B3LYP/6‐311⁺⁺G** method) to C? H lithiations with LiH or LiMe as well as to other analogue C–metal (Be, Na, Mg, Al) formations. For the borations only, this internal electrophilic substitution at carbon (S_Ei) relies more on the electrophilicity of boron than on the basicity of the internal base Y, that is, H or Me. Such direct borations of methane are more favored for dehydrogenations than for dehydrocarbonations. Due to decreased electrophilicity, substituents at boron disfavor such borations. Hence, the BH₂ group appears to be most efficient for C? H functionalizations by means of direct hydrocarbon borations.     

Accessing Ambiphilic Phosphine Boronates through C−H Borylation by an Unforeseen Cationic Iridium Complex

Ambiphilic molecules, which contain a Lewis base and Lewis acid, are of great interest based on their unique ability to activate small molecules. Phosphine boronates are one class of these substrates that have interesting catalytic activity. Direct access to these phosphine boronates is described through the iridium‐catalyzed C?H borylation of phosphines. An unconventional cationic iridium catalyst was identified as optimal for a range of phosphines, providing good yields and selectivity across a diverse class of phosphine boronates (isolated as the borane‐protected phosphine). A complimentary catalyst system (quinoline‐based silane ligand with [(COD)IrOMe]₂) was optimal for biphenyl‐based phosphines. Selective polyborylation was also shown providing bis‐ and tris‐borylated phosphines. Deprotection of the phosphine boronate provided free ambiphilic phosphine boronates, which do not have detectable interactions between the phosphorus and boron atoms in solution or the solid state.     

Catalytic Friedel–Crafts C−H Borylation of Electron‐Rich Arenes: Dramatic Rate Acceleration by Added Alkenes

In the electrophilic C−H borylation of electron‐rich aromatic compounds with catecholborane, the catalytic generation of the boron electrophile is initiated by heterolysis of the B−H bond by various Lewis and Brønsted acids, with a boronium ion formed exclusively. After ligand dissociation, the corresponding borenium ion undergoes regioselective electrophilic aromatic substitution on aniline derivatives as well as nitrogen‐containing heterocycles. The catalysis is optimized using B(C₆F₅)₃ as the initiator and proceeds without the addition of an external base or dihydrogen acceptor. Temperatures above 80 °C are generally required to secure efficient turnover in these Friedel–Crafts‐type reactions. Mechanistic experiments reveal that regeneration of the boronium/borenium ion with dihydrogen release is rate‐determining. This finding finally led to the discovery that, with added alkenes, catalytic C−H borylations can, for the first time, be carried out at room temperature.     

Interconversion of Phosphinyl Radical and Phosphinidene Complexes by Proton Coupled Electron Transfer

The isolable complex [Os(PHMes*)H(PNP)] (Mes*=2,4,6‐^tBu₃C₆H₃; PNP=N{CHCHP^tBu₂}₂) exhibits high phosphinyl radical character. This compound offers access to the phosphinidene complex [Os(PMes*)H(PNP)] by P?H proton coupled electron transfer (PCET). The P?H bond dissociation energy (BDE) was determined by isothermal titration calorimetry and supporting DFT computations. The phosphinidene product exhibits electrophilic reactivity as demonstrated by intramolecular C?H activation.     

Stereodivergent Synthesis of Arylcyclopropylamines by Sequential CH Borylation and Suzuki–Miyaura Coupling

A step‐economical and stereodivergent synthesis of privileged 2‐arylcyclopropylamines (ACPAs) through a C(sp³)? H borylation and Suzuki–Miyaura coupling sequence has been developed. The iridium‐catalyzed C? H borylation of N‐cyclopropylpivalamide proceeds with cis selectivity. The subsequent B‐cyclopropyl Suzuki–Miyaura coupling catalyzed by [PdCl₂(dppf)]/Ag₂O proceeds with retention of configuration at the carbon center bearing the Bpin group, while epimerization at the nitrogen‐bound carbon atoms of both the starting materials and products is observed under the reaction conditions. This epimerization is, however, suppressed in the presence of O₂. The present new ACPA synthesis results in not only a significant reduction in the steps required for making ACPA derivatives, but also the ability to access either isomer (cis or trans) by simply changing the atmosphere (N₂ or O₂) in the coupling stage.     

Zinc‐Catalyzed Dual C–X and C–H Borylation of Aryl Halides

A zinc‐catalyzed combined C? X and C? H borylation of aryl halides using B₂pin₂ (pin=OCMe₂CMe₂O) to produce the corresponding 1,2‐diborylarenes under mild conditions was developed. Catalytic C? H bond activation occurs ortho to the halide groups if such a site is available or meta to the halide if the ortho position is already substituted. This method thus represents a novel use of a group XII catalyst for C? H borylation. This transformation does not proceed via a free aryne intermediate, but a radical process seems to be involved.     

Electrophilic Iron Catalyst Paired with a Lithium Cation Enables Selective Functionalization of Non‐Activated Aliphatic C−H Bonds via Metallocarbene Intermediates

Combining an electrophilic iron complex [Fe(^Fpda)(THF)]₂ ( 3 ) [^Fpda=N,N′‐bis(pentafluorophenyl)‐o‐phenylenediamide] with the pre‐activation of α‐alkyl‐substituted α‐diazoesters reagents by LiAl(OR^F)₄ [OR^F=(OC(CF₃)₃] provides unprecedented access to selective iron‐catalyzed intramolecular functionalization of strong alkyl C(sp³)?H bonds. Reactions occur at 25 °C via α‐alkyl‐metallocarbene intermediates, and with activity/selectivity levels similar to those of rhodium carboxylate catalysts. Mechanistic investigations reveal a crucial role of the lithium cation in the rate‐determining formation of the electrophilic iron‐carbene intermediate, which then proceeds by concerted insertion into the C?H bond.     

Rhodium Indenyl NHC and Fluorenyl-Tethered NHC Half-Sandwich Complexes: Synthesis,Structures and Applications in the Catalytic C−H Borylation of Arenes and Alkanes

Indenyl (Ind) rhodium N-heterocyclic carbene (NHC) complexes [Rh(η⁵-Ind)(NHC)(L)] were synthesised for 1,3-bis(2,6-diisopropylphenyl)-4,5-dihydroimidazol-2-ylidene (SIPr) with L=C₂H₄ ( 1 ), CO ( 2 a ) and cyclooctene (COE; 3 ), for 1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene (SIMes) with L=CO ( 2 b ) and COE ( 4 ), and 1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene (IMes) with L=CO ( 2 c ) and COE ( 5 ). Reaction of SIPr with [Rh(Cp*)(C₂H₄)₂] did not give the desired SIPr complex, thus demonstrating the “indenyl effect” in the synthesis of 1 . Oxidative addition of HSi(OEt)₃ to 3 proceeded under mild conditions to give the Rh silyl hydride complex [Rh(Ind){Si(OEt)₃}(H)(SIPr)] ( 6 ) with loss of COE. Tethered-fluorenyl NHC rhodium complexes [Rh{(η⁵-C₁₃H₈)C₂H₄N(C)C₂H_xNR}(L)] (x=4, R=Dipp, L=C₂H₄: 11 ; L=COE: 12 ; L=CO: 13 ; R=Mes, L=COE: 14 ; L=CO: 15 ; x=2, R=Me, L=COE: 16 ; L=CO: 17 ) were synthesised in low yields (5–31 %) in comparison to good yields for the monodentate complexes (49–79 %). Compounds 3 and 1 , which contain labile alkene ligands, were successful catalysts for the catalytic borylation of benzene with B₂pin₂ (Bpin=pinacolboronate, 97 and 93 % PhBpin respectively with 5 mol % catalyst, 24 h, 80 °C), with SIPr giving a more active catalyst than SIMes or IMes. Fluorenyl-tethered NHC complexes were much less active as borylation catalysts, and the carbonyl complexes were inactive. The borylation of toluene, biphenyl, anisole and diphenyl ether proceeded to give meta substitutions as the major product, with smaller amounts of para substitution and almost no ortho product. The borylation of octane and decane with B₂pin₂ at 120 and 140 °C, respectively, was monitored by ¹¹B NMR spectroscopy, which showed high conversions into octyl and decylBpin over 4–7 days, thus demonstrating catalysed sp³ C−H borylation with new piano stool rhodium indenyl complexes. Irradiation of the monodentate complexes with 400 or 420 nm light confirmed the ready dissociation of C₂H₄ and COE ligands, whereas CO complexes were inert. Evidence for C−H bond activation in the alkyl groups of the NHC ligands was obtained.     

The Power of Iodane‐Guided C−H Coupling: A Group‐Transfer Strategy in Which a Halogen Works for Its Money

Hypervalent organoiodane reagents are ubiquitous in organic synthesis, both as oxidants and as electrophilic group‐transfer agents. In addition to these hallmark applications, a complementary strategy is gaining momentum that exploits the ability of λ³‐iodanes to undergo iodine‐to‐arene group transfer, for example, via iodonio‐Claisen‐type rearrangement processes. This Minireview discusses recent advances in the use of this method to access a variety of the C?H‐functionalized iodoarenes. While Section 2 is focused on the ortho C?H propargylation, allylation, and the more unusual para C?H benzylation, Section 3 is devoted to the C‐arylation of enol and phenol substrates. The accompanying discussion includes mechanistic considerations and goes into the synthetic applications of the final iodoarene cores. The Minireview concludes with further conceptual extensions of the method, including the use of non‐conventional coupling partners (for example, cyanoalkylation), improved access to λ³‐iodane building blocks, and the development of iterative approaches to polysubstituted iodoarenes.     

Analysis of Why Boron Avoids sp2 Hybridization and Classical Structures in the BnHn+2 Series

We performed global minimum searches for the B_nH_n+2 (n=2‐5) series and found that classical structures composed of 2c–2e B? H and B? B bonds become progressively less stable along the series. Relative energies increase from 2.9 kcal mol^?1 in B₂H₄ to 62.3 kcal mol^?1 in B₅H₇. We believe this occurs because boron atoms in the studied molecules are trying to avoid sp² hybridization and trigonal structure at the boron atoms, as in that case one 2p‐AO is empty, which is highly unfavorable. This affinity of boron to have some electron density on all 2p‐AOs and avoiding having one 2p‐AO empty is a main reason why classical structures are not the most stable configurations and why multicenter bonding is so important for the studied boron–hydride clusters as well as for pure boron clusters and boron compounds in general.     

Stereodivergent Synthesis of Arylcyclopropylamines by Sequential C?H Borylation and Suzuki–Miyaura Coupling

A step‐economical and stereodivergent synthesis of privileged 2‐arylcyclopropylamines (ACPAs) through a C(sp³) H borylation and Suzuki–Miyaura coupling sequence has been developed. The iridium‐catalyzed C H borylation of N‐cyclopropylpivalamide proceeds with cis selectivity. The subsequent B‐cyclopropyl Suzuki–Miyaura coupling catalyzed by [PdCl₂(dppf)]/Ag₂O proceeds with retention of configuration at the carbon center bearing the Bpin group, while epimerization at the nitrogen‐bound carbon atoms of both the starting materials and products is observed under the reaction conditions. This epimerization is, however, suppressed in the presence of O₂. The present new ACPA synthesis results in not only a significant reduction in the steps required for making ACPA derivatives, but also the ability to access either isomer (cis or trans) by simply changing the atmosphere (N₂ or O₂) in the coupling stage.     

Rhodium‐Catalyzed PIII‐Directed ortho‐C−H Borylation of Arylphosphines

Transition‐metal‐mediated metalation of an aromatic C?H bond that is adjacent to a tertiary phosphine group in arylphosphines via a four‐membered chelate ring was first discovered in 1968. Herein, we overcome a long‐standing problem with the ortho‐C?H activation of arylphosphines in a catalytic fashion. In particular, we developed a rhodium‐catalyzed ortho‐selective C?H borylation of various commercially available arylphosphines with B₂pin₂ through P^III‐chelation‐assisted C?H activation. This discovery is suggestive of a generic platform that could enable the late‐stage modification of readily accessible arylphosphines.     

Selective Benzylic CH-Borylations by Tandem Cobalt Catalysis

Metal-catalyzed C?H activations are environmentally and economically attractive synthetic strategies for the construction of functional molecules as they obviate the need for pre-functionalized substrates and minimize waste generation. Great challenges reside in the control of selectivities, the utilization of unbiased hydrocarbons, and the operation of atom-economical dehydrocoupling mechanisms. An especially mild borylation of benzylic CH bonds was developed with the ligand-free pre-catalyst Co[N(SiMe₃)₂]₂ and the bench-stable and inexpensive borylation reagent B₂pin₂ that produces H₂ as the only by-product. A full set of kinetic, spectroscopic, and preparative mechanistic studies are indicative of a tandem catalysis mechanism of CH-borylation and dehydrocoupling via molecular Co^I catalysts.     

Catalytic C−H Borylation Using Iron Complexes Bearing 4,5,6,7‐Tetrahydroisoindol‐2‐ide‐Based PNP‐Type Pincer Ligand

Catalytic C?H borylation has been reported using newly designed iron complexes bearing a 4,5,6,7‐tetrahydroisoindol‐2‐ide‐based PNP pincer ligand. The reaction tolerated various five‐membered heteroarenes, such as pyrrole derivatives, as well as six‐membered aromatic compounds, such as toluene. Successful examples of the iron‐catalyzed sp³ C?H borylation of anisole derivatives were also presented.     

Direct C−H Borylation of Arenes Catalyzed by Saturated Hydride-Boryl-Iridium-POP Complexes: Kinetic Analysis of the Elemental Steps

The saturated trihydride IrH₃{κ³-P,O,P-[xant(PiPr₂)₂]} ( 1 ; xant(PiPr₂)₂=9,9-dimethyl-4,5-bis(diisopropylphosphino)xanthene) activates the B−H bond of two molecules of pinacolborane (HBpin) to give H₂, the hydride-boryl derivatives IrH₂(Bpin){κ³-P,O,P-[xant(PiPr₂)₂]} ( 2 ) and IrH(Bpin)₂{κ³-P,O,P-[xant(PiPr₂)₂]} ( 3 ) in a sequential manner. Complex 3 activates a C−H bond of two molecules of benzene to form PhBpin and regenerates 2 and 1 , also in a sequential manner. Thus, complexes 1 , 2 , and 3 define two cycles for the catalytic direct C−H borylation of arenes with HBpin, which have dihydride 2 as a common intermediate. C−H bond activation of the arenes is the rate-determining step of both cycles, as the C−H oxidative addition to 3 is faster than to 2 . The results from a kinetic study of the reactions of 1 and 2 with HBpin support a cooperative function of the hydride ligands in the B−H bond activation. The addition of the boron atom of the borane to a hydride facilitates the coordination of the B−H bond through the formation of κ¹- and κ²-dihydrideborate intermediates.     

Iridium‐Catalyzed Silylation of Five‐Membered Heteroarenes: High Sterically Derived Selectivity from a Pyridyl‐Imidazoline Ligand

The steric effects of substituents on five‐membered rings are less pronounced than those on six‐membered rings because of the difference in bond angles. Thus, the regioselectivities of reactions of five‐membered heteroarenes that occur with selectivities dictated by steric effects, such as the borylation of C?H bonds, have been poor in many cases. We report that the silylation of five‐membered‐ring heteroarenes occurs with high sterically derived regioselectivity when catalyzed by the combination of [Ir(cod)(OMe)]₂ (cod=1,5‐cyclooctadiene) and a phenanthroline ligand or a new pyridyl‐imidazoline ligand that further increases the regioselectivity. The silylation reactions with these catalysts produce high yields of heteroarylsilanes from functionalization at the most sterically accessible C?H bonds of these rings under conditions that the borylation of C?H bonds with previously reported catalysts formed mixtures of products or products that are unstable. The heteroarylsilane products undergo cross‐coupling reactions and substitution reactions with ipso selectivity to generate heteroarenes that bear halogen, aryl, and perfluoroalkyl substituents.