Balancing Reactivity, Regioselectivity, and Product Stability in Ir-Catalyzed Ortho-C-H Borylations of Anilines by Modulating the Diboron Partner.

Ir-catalyzed arene C-H borylations (CHB) of anilines can be highly ortho selective by using a small B2eg2 (eg = ethane-1,2-diol) as the borylating reagent. Unfortunately, the products are prone to decomposition, and transesterification with pinacol is required prior to isolation. This work offers a solution by adjusting the size of the diboron reagent. Based on our evaluation, we conclude that B2bg2 (bg = butane-1,2-diol) achieves an optimal balance between CHB regioselectivity and stability for the borylated products.

A Hydrazone Ligand for Iridium-Catalyzed C-H Borylation: Enhanced Reactivity and Selectivity for Fluorinated Arenes.

Ir-catalyzed C-H borylations of fluorinated and cyanated arenes with high meta-to-F/CN are described. Use of a dipyridyl hydrazone framework as the ancillary ligand and pinacolborane (HBpin) as the functionalizing reagent generates catalysts that are significantly more active and selective than 4,4'-di-tert-butyl-2,2'-bipyridine (dtbpy) for both electron-deficient and electron-rich substrates. Investigation of the ligand framework resulted in the observation of formal N-borylation of the hydrazone by HBpin, as evidenced by NMR spectroscopy and X-ray crystallography. Subsequent stoichiometric reactions of this adduct with an iridium precatalyst revealed the formation of an unusual IrI hydrazido. Isolation and use of this hydrazido reproduce the selectivity of in situ generated catalysts, suggesting that it leads to formation of the active species.

Access to C(sp3) borylated and silylated cyclic molecules: hydrogenation of corresponding arenes and heteroarenes.

This paper presents a simple and cost-effective hydrogenation method for synthesizing a myriad of cycloalkanes and saturated heterocycles bearing boryl or silyl substituents. The catalyst used are heterogeneous, readily available, bench stable, and recyclable. Also demonstrated is the application of the method to compounds that possess both boryl and silyl groups. When combined with Ir-catalyzed sp2 C-H borylation, such hydrogenations offer a two-step complementary alternative to direct sp3 C-H borylations that can suffer selectivity and reactivity issues. Of practical value to the community, complete stereochemical analyses of reported borylated compounds that were never fully characterized are reported herein.

Simple and Green Preparation of Tetraalkoxydiborons and Diboron Diolates from Tetrahydroxydiboron.

Tetraalkoxydiborons can be easily prepared by acid-catalyzed reactions of tetrahydroxydiboron or its anhydride with trialkyl orthoformates. Addition of diols to these reaction mixtures afforded diboron diolates in high yield. In both cases, removal of volatile byproducts is all that is required for the isolation of the diboron. These methods constitute a convenient alternative to previous preparations from tetrakis (dimethylamino) diboron and tetrahydroxydiboron.

Regiochemical Switching in Ir-Catalyzed C-H Borylation by Altering Ligand Loadings of N,B-Type Diboron Species.

Traditional reaction conditions in Ir-catalyzed C-H borylation consist of a 2:1 ligand to Ir metal ratio, affording C(sp2)-H borylation at the least sterically hindered position. We found that lowering the ligand to metal ratio of a N,B-type diboron (BB) preligand in respect to the IrI precatalyst to 0.5:1 affords the chelate controlled ortho product. Switching from steric-directed to chelate-directed products is shown for various substituted arenes and (hetero)arenes containing Lewis-basic functionalities. This work offers the first example of obtaining complementary regioisomers as the major product by altering the ligand loading in CHB.

Merging Iridium-Catalyzed C-H Borylations with Palladium-Catalyzed Cross-Couplings Using Triorganoindium Reagents.

A versatile and efficient method to prepare borylated arenes furnished with alkyl, alkenyl, alkynyl, aryl, and heteroaryl functional groups is developed by merging Ir-catalyzed C-H borylations (CHB) with a chemoselective palladium-catalyzed cross-coupling of triorganoindium reagents (Sarandeses-Sestelo coupling) with aryl halides bearing a boronic ester substituent. Using triorganoindium cross-coupling reactions to introduce unsaturated moieties enables the synthesis of borylated arenes that would be difficult to access through the direct application of the CHB methodology. The sequential double catalyzed procedure can be also performed in one vessel.

Steric Shielding Effects Induced by Intramolecular C-H⋯O Hydrogen Bonding: Remote Borylation Directed by Bpin Groups.

Regioselectivities in catalytic C-H borylations (CHBs) have been rationalized using simplistic steric models and correlations with nuclear magnetic resonance (NMR) chemical shifts. However, regioselectivity can be significant for important substrate classes where none would be expected from these arguments. In this study, intramolecular hydrogen bonding (IMHB) can lead to steric shielding effects that can direct Ir-catalyzed CHB regiochemistry. Bpin (Bpin = pinacol boronic ester)/arene IMHB can promote remote borylations of N-borylated anilines, 2-amino-N-alkylpyridine, tetrahydroquinolines, indoles, and 1-borylated naphthalenes. Experimental and computational studies support molecular geometries with the Bpin orientation controlled by a C-H⋯O IMHB. IMHB-directed remote CHB appeared operative in the C6 borylation of 3-aminoindazole (seven-membered IMHB) and C6 borylation of an osimertinib analogue where a pyrimidine IMHB creates the steric shield. This study informs researchers to evaluate not only inter- but also intramolecular noncovalent interactions as potential drivers of remote CHB regioselectivity.

Amide directed iridium C(sp3)-H borylation catalysis with high N-methyl selectivity.

A bidentate monoanionic ligand system was developed to enable iridium catalyzed C(sp3)-H activation borylation of N-methyl amides. Borylated amides were obtained in moderate to good isolated yields, and exclusive mono-borylation allowed the amide to be the limiting reagent. Selectivity for C(sp3)-H activation was demonstrated in the presence of sterically available C(sp3)-H bonds. Competitive kinetic isotope studies revealed a large primary isotope effect, implicating C-H activation as the rate limiting step.

Silylcyclopropanes by Selective [1,4]-Wittig Rearrangement of 4-Silyl-5,6-dihydropyrans.

4-Silyl-5,6-dihydropyrans undergo remarkably selective [1,4]-Wittig rearrangements to give silylcyclopropanes in good yields. The selectivity is independent of the silyl group, but it is influenced by the electronic character of the migrating center. Electron-rich and electron-neutral (hetero)aryl groups and aliphatic substituents at the migrating center lead to exclusive [1,4]-migration, whereas electron-deficient aryl groups predominantly afford [1,2]-Wittig products.

One-Pot Iridium Catalyzed C-H Borylation/Sonogashira Cross-Coupling: Access to Borylated Aryl Alkynes.

Borylated aryl alkynes have been synthesized via one-pot iridium catalyzed C-H borylation (CHB)/Sonogashira cross-coupling of aryl bromides. Direct borylation of aryl alkynes encountered problems related to the reactivity of the alkyne under CHB conditions. However, tolerance of aryl bromides to CHB made possible a subsequent Sonogashira cross-coupling to access the desired borylated aryl alkynes.

Para-Selective, Iridium-Catalyzed C-H Borylations of Sulfated Phenols, Benzyl Alcohols, and Anilines Directed by Ion-Pair Electrostatic Interactions.

Para C-H borylations (CHB) of tetraalkylammonium sulfates and sulfamates have been achieved using bipyridine-ligated Ir boryl catalysts. Selectivities can be modulated by both the length of the alkyl groups in the tetraalkylammonium cations and the substituents on the bipyridine ligands. Ion pairing, where the alkyl groups of the cation shield the meta C-H bonds in the counteranions, is proposed to account for para selectivity. The 4,4'-dimethoxy-2,2'-bipyridine ligand gave superior selectivities.

C-H Borylation Catalysts that Distinguish Between Similarly Sized Substituents Like Fluorine and Hydrogen.

By modifying ligand steric and electronic profiles it is possible to C-H borylate ortho or meta to substituents in aromatic and heteroaromatic compounds, where steric differences between accessible C-H sites are small. Dramatic effects on selectivities between reactions using B2pin2 or 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (HBpin) are described for the first time. Judicious ligand and borane combinations give highly regioselective C-H borylations on substrates where typical borylation protocols afford poor selectivities.

A general diversity oriented synthesis of asymmetric double-decker shaped silsesquioxanes.

A strategically novel synthesis of nano-sized, asymmetrically functionalized double-decker shaped silsesquioxanes (DDSQ) is reported. Selective protection with a boronic acid affords the crucial mono-protected intermediate en route to the asymmetric products. Generation of symmetric by-products is minimized by judicious choice of base, and high recovery of recyclable starting DDSQ tetraol is achieved.

Achieving High Ortho Selectivity in Aniline C-H Borylations by Modifying Boron Substituents.

High ortho selectivity for Ir-catalyzed C-H borylations (CHBs) of anilines results when B2eg2 (eg = ethylene glycolate) is used as the borylating reagent in lieu of B2pin2, which is known to give isomeric mixtures with anilines lacking a blocking group at the 4-position. With this modification, high selectivities and good yields are now possible for various anilines, including those with groups at the 2- and 3-positions. Experiments indicate that ArylN(H)Beg species are generated prior to CHB and support the improved ortho selectivity relative to B2pin2 reactions arising from smaller Beg ligands on the Ir catalyst. The lowest-energy transition states (TSs) from density functional theory computational analyses have N-H···O hydrogen-bonding interactions between PhN(H)Beg and O atoms in Beg ligands. Ir-catalyzed CHB of PhN(H)Me with B2eg2 is also highly ortho-selective. 1H NMR experiments show that N-borylation fully generates PhN(Me)Beg prior to CHB. The TS with the lowest Gibbs energy was the ortho TS, in which the Beg unit is oriented anti to the bipyridine ligand.

Ir-Catalyzed ortho-Borylation of Phenols Directed by Substrate-Ligand Electrostatic Interactions: A Combined Experimental/in Silico Strategy for Optimizing Weak Interactions.

A strategy for affecting ortho versus meta/para selectivity in Ir-catalyzed C-H borylations (CHBs) of phenols is described. From selectivity observations with ArylOBpin (pin = pinacolate), it is hypothesized that an electrostatic interaction between the partial negatively charged OBpin group and the partial positively charged bipyridine ligand of the catalyst favors ortho selectivity. Experimental and computational studies designed to test this hypothesis support it. From further computational work a second generation, in silico designed catalyst emerged, where replacing Bpin with Beg (eg = ethylene glycolate) was predicted to significantly improve ortho selectivity. Experimentally, reactions employing B2eg2 gave ortho selectivities > 99%. Adding triethylamine significantly improved conversions. This ligand-substrate electrostatic interaction provides a unique control element for selective C-H functionalization.

Bismuth Acetate as a Catalyst for the Sequential Protodeboronation of Di- and Triborylated Indoles.

Bismuth(III) acetate is a safe, inexpensive, and selective facilitator of sequential protodeboronations, which when used in conjunction with Ir-catalyzed borylations allows access to a diversity of borylated indoles. The versatility of combining Ir-catalyzed borylations with Bi(III)-catalyzed protodeboronation is demonstrated by selectively converting 6-fluoroindole into products with Bpin groups at the 4-, 5-, 7-, 2,7-, 4,7-, 3,5-, and 2,4,7-positions and the late-stage functionalization of sumatriptan.

Harnessing C-H Borylation/Deborylation for Selective Deuteration, Synthesis of Boronate Esters, and Late Stage Functionalization.

Ir-catalyzed deborylation can be used to selectively deuterate aromatic and heteroaromatic substrates. Combined with the selectivities of Ir-catalyzed C-H borylations, uniquely labeled compounds can be prepared. In addition, diborylation/deborylation reactions provide monoborylated regioisomers that complement those prepared by C-H borylation. Comparisons between Ir-catalyzed deborylations and Pd-catalyzed deborylations of diborylated indoles described by Movassaghi are made. The Ir-catalyzed process is more effective for deborylating aromatics and is generally more effective in the monodeborylation of diborylated thiophenes. These processes can be applied to complex molecules such as clopidogrel.

Reversible Borylene Formation from Ring Opening of Pinacolborane and Other Intermediates Generated from Five-Coordinate Tris-Boryl Complexes: Implications for Catalytic C-H Borylation.

Catalytic C-H borylation using the five-coordinate tris-boryl complex (dippe)Ir(Bpin)3 (5a, dippe = 1,2-bis(diisopropylphosphino)ethane) has been examined using 31P{1H} and 1H NMR spectroscopy. Compound 5a was shown to react rapidly and reversibly with HBpin to generate a six-coordinate borylene complex, (dippe)Ir(H)-(Bpin)2(BOCMe2CMe2OBpin) (6), whose structure was confirmed by X-ray crystallography. Under catalytic conditions, the H2 generated from C-H borylation converted compound 6 to a series of intermediates. The first is tentatively assigned from 31P{1H} and 1H NMR spectra as (dippe)Ir(H2B3pin3) (7), which is the product of formal H2 addition to compound 5a. As catalysis progressed, compound 7 was converted to a new species with the formula (dippe)Ir(H3B2pin2) (8), which arose from H2 addition to compound 7 with loss of HBpin. Compound 8 was characterized by 31P{1H} and 1H NMR spectroscopy, and its structure was confirmed by X-ray crystallography, where two molecules with different ligand orientations were found in the unit cell. DFT calculations support the formulation of compound 8 as an IrIII agostic borane complex, (dippe)IrH2(Bpin)(η2-HBpin). Compound 8 was gradually converted to (dippe)Ir(H4Bpin) (9), which was characterized by 31P{1H} and 1H NMR spectroscopy and X-ray crystallography. DFT calculations favor its formulation as an agostic borane complex of IrIII with the formula (dippe)IrH3(η2-HBpin). Compound 9 reacted further with H2 to afford the dimeric structure [(dippe)IrH2(µ2-H)]2 (10), which was characterized by 1H NMR and X-ray crystallography. Compounds 7-10 are in equilibrium when H2 and HBpin are present.

Stereoconvergent [1,2]- and [1,4]-Wittig rearrangements of 2-silyl-6-aryl-5,6-dihydropyrans: a tale of steric vs electronic regiocontrol of divergent pathways.

The regiodivergent ring contraction of diastereomeric 2-silyl-5,6-dihydro-6-aryl-(2H)-pyrans via [1,2]- and [1,4]-Wittig rearrangements to the corresponding α-silylcyclopentenols or (α-cyclopropyl)acylsilanes favor the [1,4]-pathway by ortho and para directing groups in the aromatic appendage and/or by sterically demanding silyl groups. The [1,2]-pathway is dominant with meta directing or electron-poor aromatic moieties. Exclusive [1,2]-Wittig rearrangements are observed when olefin substituents proximal to the silyl are present. cis and trans diastereomers exhibit different reactivities, but converge to a single [1,2]- or [1,4]-Wittig product with high diastereoselectivity and yield.

A catalytic borylation/dehalogenation route to o-fluoro arylboronates.

A two-step Ir-catalyzed borylation/Pd-catalyzed dehalogenation sequence allows for the net synthesis of fluoroarenes where the boronic ester is ortho to fluorine. Key elements of this approach include the use of a halogen para to the fluorine to block meta Ir-catalyzed borylation and the chemoselective Pd-catalyzed dehalogenation by KF activated polymethylhydrosiloxane (PMHS).