Heteroaryl Boronic Esters Research Articles

Construction of Heterobiaryl Skeletons through Pd-Catalyzed Cross-Coupling of Nitroarenes and Heterocyclic Arylborononate Esters with a Sterically Demanding NHC Ligand.

The palladium-catalyzed Suzuki-Miyaura cross-couplings of nitroarenes and heteroarylboronate esters has been developed. A number of heterobiaryl compounds containing pyridine, pyrimidine, quinoline, furan, thiophene, and pyrazole were prepared using [Pd(cinnamyl)Cl]2/2-aryl-5-(2,4,6-triisopropylphenyl)-2,3-imidazolylidene[1,5-a]pyridines as the catalysts in good to excellent yields. The synthetic practicality of this approach is demonstrated through the synthesis of druglike molecules.

Heteroaryl-Heteroaryl, Suzuki-Miyaura, Anhydrous Cross-Coupling Reactions Enabled by Trimethyl Borate.

Reaction conditions have been developed for refractory heteroaryl-heteroaryl Suzuki-Miyaura cross-couplings. The reported method employs neopentyl heteroarylboronic esters as nucleophiles, heteroaryl bromides and chlorides as the electrophiles, and the soluble base potassium trimethylsilanolate (TMSOK) under anhydrous conditions. The addition of trimethyl borate enhances reaction rates by several mechanisms, including (1) solubilization of in situ-generated boronate complexes, (2) preventing catalyst poisoning by the heteroatomic units, and (3) buffering the inhibitory effect of excess TMSOK. The use of this method enables cross-coupling of diverse reaction partners including a broad range of π-rich and π-deficient heteroaryl boronic esters and heteroaryl bromides. Reactions proceed in good yields and short reaction times (3 h or less).

Copper-Catalyzed Enantioconvergent Radical Suzuki-Miyaura C(sp3)-C(sp2) Cross-Coupling.

A copper-catalyzed enantioconvergent Suzuki-Miyaura C(sp3)-C(sp2) cross-coupling of various racemic alkyl halides with organoboronate esters has been established in high enantioselectivity. Critical to the success is the use of a chiral cinchona alkaloid-derived N,N,P-ligand for not only enhancing the reducing capability of copper catalyst to favor a stereoablative radical pathway over a stereospecific SN2-type process but also providing an ideal chiral environment to achieve the challenging enantiocontrol over the highly reactive radical species. The reaction has a broad scope with respect to both coupling partners, covering aryl- and heteroarylboronate esters, as well as benzyl-, heterobenzyl-, and propargyl bromides and chlorides with good functional group compatibility. Thus, it provides expedient access toward a range of useful enantioenriched skeletons featuring chiral tertiary benzylic stereocenters.

Hydrogenation of (Hetero)aryl Boronate Esters with a Cyclic (Alkyl)(amino)carbene-Rhodium Complex: Direct Access to cis-Substituted Borylated Cycloalkanes and Saturated Heterocycles.

We herein report the hydrogenation of substituted aryl- and heteroaryl boronate esters for the selective synthesis of cis-substituted borylated cycloalkanes and saturated heterocycles. A cyclic (alkyl)(amino)carbene-ligated rhodium complex with two dimethyl groups at the ortho-alkyl scaffold of the carbene showed high reactivity in promoting the hydrogenation, thereby enabling the hydrogenation of (hetero)arenes with retention of the synthetically valuable boronate group. This process constitutes a clean, atom-economic, as well as chemo- and stereoselective route for the generation of cis-configured, diversely substituted borylated cycloalkanes and saturated heterocycles that are usually elusive and difficult to prepare.

Hydrogenation of (Hetero)aryl Boronate Esters with a Cyclic (Alkyl)(amino)carbene–Rhodium Complex: Direct Access to cis‐Substituted Borylated Cycloalkanes and Saturated Heterocycles

AbstractWe herein report the hydrogenation of substituted aryl‐ and heteroaryl boronate esters for the selective synthesis of cis‐substituted borylated cycloalkanes and saturated heterocycles. A cyclic (alkyl)(amino)carbene‐ligated rhodium complex with two dimethyl groups at the ortho‐alkyl scaffold of the carbene showed high reactivity in promoting the hydrogenation, thereby enabling the hydrogenation of (hetero)arenes with retention of the synthetically valuable boronate group. This process constitutes a clean, atom‐economic, as well as chemo‐ and stereoselective route for the generation of cis‐configured, diversely substituted borylated cycloalkanes and saturated heterocycles that are usually elusive and difficult to prepare.

Trimethylphosphate as a Methylating Agent for Cross Coupling: A Slow-Release Mechanism for the Methylation of Arylboronic Esters.

A methyl group on an arene, despite its small size, can have a profound influence on biologically active molecules. Typical methods to form a methylarene involve strong nucleophiles or strong and often toxic electrophiles. We report a strategy for a new, highly efficient, copper and iodide co-catalyzed methylation of aryl- and heteroarylboronic esters with the mild, nontoxic reagent trimethylphosphate, which has not been used previously in coupling reactions. We show that it reacts in all cases tested in yields that are higher than those of analogous copper-catalyzed reactions of MeOTs or MeI. The combination of C-H borylation and this methylation with trimethylphosphate provides a new approach to the functionalization of inert C-H bonds and is illustrated by late-stage methylation of four medicinally active compounds. In addition, reaction on a 200 mmol scale demonstrates reliability of this method. Mechanistic studies show that the reaction occurs by a slow release of methyl iodide by reaction of PO(OMe)3 with iodide catalyst, rather than the typical direct oxidative addition to a metal center. The low concentration of the reactive electrophile enables selective reaction with an arylcopper intermediate, rather than nucleophilic groups on the arylboronate, and binding of tert-butoxide to the boronate inhibits reaction of the electrophile with the tert-butoxide activator to form methyl ether.

Micelle-Enabled Suzuki-Miyaura Cross-Coupling of Heteroaryl Boronate Esters.

We report a micellar protocol for Suzuki-Miyaura cross-coupling of heteroaryl boronic esters with aryl or heteroaryl halides. The micellar catalysis enables this coupling reaction to run under mild conditions, which avoids the decomposition of heteroaryl boronate esters and allows for high chemoselectivity for cross-coupling reaction with 6-chloropridine-2-boronic ester. The micellar protocol expands the scope of the cross-coupling reaction with challenging heteroaryl boronic esters and complements the existing cross-coupling methods for construction of heterobiaryl building blocks.

Ambiphilic Molecules: From Organometallic Curiosity to Metal-Free Catalysts.

Ambiphilic molecules were first used as functional ligands for transition elements, which could enable intriguing organometallic transformations. In the past decade, these intramolecular Lewis pairs, first considered organometallic curiosities, have become staples in organometallic chemistry and catalysis, acting as Z ligands, activating inert molecules using the concept of frustrated Lewis pair (FLP) chemistry, and acting as metal-free catalysts. In this Account, we detail our contribution to this blossoming field of research, focusing on the use of ambiphilic molecules as metal-free catalysts for CO2 reduction and C-H borylation reactions. A major emphasis is put on the mechanistic investigations we carried out using reactivity studies and theoretical tools, which helped us steer our research from stoichiometric transformations to highly active catalytic processes. We first report the interaction of aluminum-phosphine ambiphilic molecules with carbon dioxide. Although these Lewis pairs can bind CO2, a study of the deactivation process in the presence of CO2 and hydroboranes led us to discover that simple phosphinoborane molecules could act as active precatalysts for the hydroboration of carbon dioxide into methanol precursors. In these systems, the Lewis basic sites interact with the reducing agents rather than with the electrophilic carbon of CO2, increasing the nucleophilicity of hydroboranes. Simultaneously, the weak Lewis acids stabilize the oxygen of the gas molecule in the transition state, leading to high reaction rates. Replacing the phosphine by an amine leads to a system enabling CO2 hydrogenation, albeit only in stoichiometric transformations. Investigation of the protodeborylation deactivation of aminoboranes led us to develop metal-free catalysts for the C-H borylation of heteroarenes. By protecting the Lewis acid sites of these catalysts using fluoride, we were able to synthesize practical, air-stable precatalysts allowing the convenient synthesis of heteroarylboronic esters on a multigram scale. Contrary to general perception of FLP chemistry, we also demonstrated that a significant increase in activity could be obtained by reducing the steric bulk around the active site. These smaller systems exist as stable dimers and are more energetically costly to dissociate into active FLPs, but the approach of the substrate and the C-H activation step are significantly favored compared to the bulkier analogues. An in-depth study of the stability and reactivity of these aminoborane molecules also allowed us to develop a metal-free catalytic S-H bond borylation system, and to report stoichiometric and spontaneous B-B bond formation and Csp3-H bond activation processes, highlighting the importance of H2 release as a thermodynamic driving force in these FLP transformations.

Fine-tuning the nucleophilic reactivities of boron ate complexes derived from aryl and heteroaryl boronic esters.

Boron ate complexes derived from thienyl and furyl boronic esters and aryllithium compounds have been isolated and characterized by X-ray crystallography. Products and mechanisms of their reactions with carbenium and iminium ions have been analyzed. Kinetics of these reactions were monitored by UV/Vis spectroscopy, and the influence of the aryl substituents, the diol ligands (pinacol, ethylene glycol, neopentyl glycol, catechol), and the counterions on the nucleophilic reactivity of the boron ate complexes were examined. A Hammett correlation confirmed the polar nature of their reactions with benzhydrylium ions, and the correlation lg k(20 °C)=sN (E+N) was employed to determine the nucleophilicities of the boron ate complexes and to compare them with those of other borates and boronates. The neopentyl and ethylene glycol derivatives were found to be 10(4) times more reactive than the pinacol and catechol derivatives.

ChemInform Abstract: Copper‐Catalyzed Suzuki—Miyaura Coupling of Arylboronate Esters: Transmetalation with (PN)CuF and Identification of Intermediates.

An efficient CuI-catalyzed Suzuki–Miyaura reaction was developed for the coupling of aryl- and heteroarylboronate esters with aryl and heteroaryl iodides at low catalyst loadings (2 mol %). The reaction proceeds under ligand-free conditions for aryl–heteroaryl and heteroaryl–heteroaryl couplings. We also conducted the first detailed mechanistic studies by synthesizing [(PN-2)CuI]2, [(PN-2)CuF]2, and (PN-2)CuPh (PN-2 = o-(di-tert-butylphosphino)-N,N-dimethylaniline) and demonstrated that [(PN-2)CuF]2 is the species that undergoes transmetalation with arylboronate esters.

Iridium-Catalyzed C–H Borylation of Heteroarenes: Scope, Regioselectivity, Application to Late-Stage Functionalization, and Mechanism

A study on the iridium-catalyzed C-H borylation of heteroarenes is reported. Several heteroarenes containing multiple heteroatoms were found to be amenable to C-H borylation catalyzed by the combination of an iridium(I) precursor and tetramethylphenanthroline. The investigations of the scope of the reaction led to the development of powerful rules for predicting the regioselectivity of borylation, foremost of which is that borylation occurs distal to nitrogen atoms. One-pot functionalizations are reported of the heteroaryl boronate esters formed in situ, demonstrating the usefulness of the reported methodology for the synthesis of complex heteroaryl structures. Application of this methodology to the synthesis and late-stage functionalization of biologically active compounds is also demonstrated. Mechanistic studies show that basic heteroarenes can bind to the catalyst and alter the resting state from the olefin-bound complex observed during arene borylation to a species containing a bound heteroarene, leading to catalyst deactivation. Studies on the origins of the observed regioselectivity show that borylation occurs distal to N-H bonds due to rapid N-H borylation, creating an unfavorable steric environment for borylation adjacent to these bonds. Computational studies and mechanistic studies show that the lack of observable borylation of C-H bonds adjacent to basic nitrogen is not the result of coordination to a bulky Lewis acid prior to C-H activation, but the combination of a higher-energy pathway for the borylation of these bonds relative to other C-H bonds and the instability of the products formed from borylation adjacent to basic nitrogen.

Copper-Catalyzed Suzuki–Miyaura Coupling of Arylboronate Esters: Transmetalation with (PN)CuF and Identification of Intermediates

An efficient Cu(I)-catalyzed Suzuki-Miyaura reaction was developed for the coupling of aryl- and heteroarylboronate esters with aryl and heteroaryl iodides at low catalyst loadings (2 mol %). The reaction proceeds under ligand-free conditions for aryl-heteroaryl and heteroaryl-heteroaryl couplings. We also conducted the first detailed mechanistic studies by synthesizing [(PN-2)CuI]2, [(PN-2)CuF]2, and (PN-2)CuPh (PN-2 = o-(di-tert-butylphosphino)-N,N-dimethylaniline) and demonstrated that [(PN-2)CuF]2 is the species that undergoes transmetalation with arylboronate esters.

Ruthenium‐Catalyzed α‐(Hetero)Arylation of Saturated Cyclic Amines: Reaction Scope and Mechanism

Transition-metal-catalyzed sp(3) C-H activation has emerged as a powerful approach to functionalize saturated cyclic amines. Our group recently disclosed a direct catalytic arylation reaction of piperidines at the α position to the nitrogen atom. 1-(Pyridin-2-yl)piperidine could be smoothly α-arylated if treated with an arylboronic ester in the presence of a catalytic amount of [Ru3(CO)12] and one equivalent of 3-ethyl-3-pentanol. A systematic study on the substrate and reagent scope of this transformation is disclosed in this paper. The effect of substitution on both the piperidine ring and the arylboronic ester has been investigated. Smaller (pyrrolidine) and larger (azepane) saturated ring systems, as well as benzoannulated derivatives, were found to be compatible substrates with the α-arylation protocol. The successful use of a variety of heteroarylboronic esters as coupling partners further proved the power of this direct functionalization method. Mechanistic studies have allowed for a better understanding of the catalytic cycle of this remarkable transformation featuring an unprecedented direct transmetalation on a Ru(II)-H species.

Retention or inversion in stereospecific nickel-catalyzed cross-coupling of benzylic carbamates with arylboronic esters: control of absolute stereochemistry with an achiral catalyst.

Stereospecific coupling of benzylic carbamates and pivalates with aryl- and heteroarylboronic esters has been developed. The reaction proceeds with selective inversion or retention at the electrophilic carbon, depending on the nature of the ligand. Tricyclohexylphosphine ligand provides the product with retention, while an N-heterocyclic carbene ligand provides the product with inversion.