Tandem cycloisomerization/Suzuki coupling of arylethynyl MIDA boronates

A tandem gold-catalyzed cycloisomerization/Suzuki cross-coupling sequence involving arylethynyl-N-methyliminodiacetic acid boronates is described. Combining the mildness of homogeneous gold catalysis with the versatility of N-methyliminodiacetic acid (MIDA) boronates, this tandem two-step method enables the rapid assembly of various aryl-substituted heterocycles without having to isolate or purify any heterocyclic MIDA boronate intermediates. Another major advantage of this method is that a wide range of heterocycles bearing different aryl groups may be made from a single MIDA boronate alkyne precursor.     

Vinyl MIDA boronate: a readily accessible and highly versatile building block for small molecule synthesis

Iterative cross-coupling represents a potentially general approach for the simple, efficient, and flexible construction of natural products, pharmaceuticals, and materials. N-Methyliminodiacetic acid (MIDA) boronates represent a promising platform for the development of this type of synthesis strategy. This report describes the discovery that vinyl MIDA boronate (1) is an air- and chromatographically stable compound that can be conveniently prepared on a multigram scale and serve as a versatile starting material for the preparation of a range of new MIDA boronate building blocks. Analogous to tert-butylethylene, 1 is also an excellent substrate for olefin cross-metathesis, providing access to a range of trans-alkenyl MIDA boronates as single stereoisomers. An improved synthesis of the very versatile bifunctional building block trans-(2-bromovinyl) MIDA boronate (2) is also described. Collectively, these results contribute to the expanding generality of the iterative cross-coupling approach.     

Regioselective synthesis and slow-release Suzuki-Miyaura cross-coupling of MIDA boronate-functionalized isoxazoles and triazoles

The efficient preparation of heterocycles with a range of substitutions ortho to heteroatoms remains as a challenge in organic synthesis, particularly relevant to the construction of druglike molecules due to the ubiquitous presence of such moieties in that chemical space. Modular installation of heterocyclic building blocks using Suzuki-Miyaura cross-coupling is a conceptually useful strategy to address this challenge, though this has historically been met with technical difficulty due to issues of inaccessibility and instability of the requisite heterocyclic boronates. Herein we report a mild and highly regioselective cycloaddition approach which affords convenient access to stable MIDA boronate-functionalized isoxazoles and triazoles and their subsequent efficient Suzuki-Miyaura cross-coupling. This methodology is then further applied to a set of druglike compounds in an efficient one-pot telescoped sequence in line with green chemistry principles.     

Multistep synthesis of complex boronic acids from simple MIDA boronates

Due to its sensitivity to most synthetic reagents, it is typically necessary to introduce the boronic acid functional group just prior to its utilization. Overcoming this important limitation, we herein report that air- and chromatographically stable MIDA boronates are compatible with a wide range of common reagents which enables the multistep synthesis of complex boronic acid building blocks from simple B-containing starting materials. X-ray and variable temperature NMR studies link the unique stability of MIDA boronates to a kinetic inaccessibility of the potentially reactive boron p-orbital and/or nitrogen lone pair. These findings were collectively harnessed to achieve a short and modular total synthesis of (+)-crocacin C via the iterative cross-coupling of a structurally complex, MIDA-protected haloboronic acid building block.     

(Z)-(2-bromovinyl)-MIDA boronate: a readily accessible and highly versatile building block for small molecule synthesis

Iterative cross-coupling represents a potentially general approach for the simple, efficient, and flexible construction of a wide range of functional small molecules. In this context, (Z)-(2-bromovinyl)-N-methyliminodiacetic acid (MIDA) boronate is a very useful building block for small molecule synthesis. This compound can serve as a starting material for the preparation of a wide range of cis-alkene-containing MIDA boronates. This compound can also be used for the iterative cross-coupling-based synthesis of various cis-olefin-containing targets. Collectively, these results contribute to the expanding generality of the MIDA boronate platform.     

Cation exchange media provide a multi-stage,orthogonal catch and release method for MIDA boronates bearing basic centers

An operationally simple and rapid purification of MIDA boronates is described. This method allows separation of MIDA boronates containing basic centers from those that are neutral as well as separation from species that do not contain the MIDA moiety using a single “catch and release” purification medium. Application of this method to the purification of reductive amination products is described. It is hoped that this facile, rapid and conceptually new isolation will stimulate further investigation of other functionalized silica gel media for the isolation of MIDA boronate building blocks.     

Direct Access to MIDA Acylboronates through Mild Oxidation of MIDA Vinylboronates

Acylboronate esters/trifluoroborates represent an elusive class of boronates that are of increasing interest for both fundamental study as well as applications at the interface of chemistry and biology. Their preparation has been limited by the use of strongly basic anions, often introduced in multistep reactions. Herein, we demonstrate the facile preparation of acylboronate N‐methyliminodiacetyl (MIDA) esters from alkenyl‐2‐boronate esters through mild dihydroxylation and meta ‐periodate cleavage. Given the well‐known functional‐group tolerance of this mild reaction sequence and the availability of alkenyl‐2‐boronates, this method should greatly increase access to acylboronate MIDA esters.     

Stereoselective Direct Chlorination of Alkenyl MIDA Boronates: Divergent Synthesis of E and Z α‐Chloroalkenyl Boronates

The individual molecules of α‐chloroalkenyl boronates include both an electrophilic C−Cl bond and a nucleophilic C−B bond, which makes them intriguing organic synthons. Reported herein is a stereodivergent synthesis of both E and Z α‐chloroalkenyl N ‐methyliminodiacetyl (MIDA) boronates through the direct chlorination of alkenyl MIDA boronates using t BuOCl and PhSeCl reagents, respectively. Both reaction processes are stereospecific and the use of sp³‐B MIDA boronate is the key contributor to the reactivity. The synthetic value of the boronate products was also demonstrated.     

Diversity‐Oriented Synthesis of α‐Functionalized Acylborons and Borylated Heteroarenes by Nucleophilic Ring Opening of α‐Chloroepoxyboronates

The ring‐opening reactions of N‐methyliminodiacetyl (MIDA) α‐chloroepoxyboronates with different nucleophiles allow the modular synthesis of a diverse array of organoboronates. These include seven types of α‐functionalized acylboronates and seven types of borylated heteroarenes, some of which are difficult‐to‐access products using alternative methods. The common synthons, α‐chloroepoxyboronates, could be viably synthesized by a two‐step procedure from the corresponding alkenyl MIDA boronates. Mild reaction conditions, good functional‐group tolerance, and generally good efficiency were observed. The utility of the products was also demonstrated.     

Synthesis of Aminoboronic Acid Derivatives from Amines and Amphoteric Boryl Carbonyl Compounds

Herein, we demonstrate the use of α‐boryl aldehydes and acyl boronates in the synthesis of aminoboronic acid derivatives. This work highlights the untapped potential of boron‐substituted iminium ions and offers insights into the behavior of N‐methyliminodiacetyl (MIDA) boronates during condensation and tautomerization processes. The preparative value of this contribution lies in the demonstration that various amines, including linear and cyclic peptides, can be readily conjugated with boron‐containing fragments. A mild deprotection of amino MIDA‐boronates enables access to α‐ and β‐aminoboronic acids in high chemical yields. This simple process should be applicable to the synthesis of a wide range of bioactive molecules as well as precursors for cross‐coupling reactions.     

Oxidative Difunctionalization of Alkenyl MIDA Boronates: A Versatile Platform for Halogenated and Trifluoromethylated α‐Boryl Ketones

The synthesis of halogenated and trifluoromethylated α‐boryl ketones via a one‐pot oxidative difunctionalization of alkenyl MIDA boronates is reported. These novel densely functionalized organoborons bearing synthetically and functionally valuable carbonyl, halogen/CF₃ and boronate moieties within the same molecule are synthetically challenging for the chemist, but have great synthetic potential, as demonstrated by their applications in a straightforward synthesis of borylated furans. The generality of this reaction was extensively investigated. This reaction is attractive since the starting materials, alkenyl MIDA boronates, are easily accessible.     

Suzuki-Miyaura cross-coupling of alkenyl tosylates with alkenyl MIDA boronates

A practical procedure for the palladium-catalysed Suzuki-Miyaura coupling of various alkenyl tosylates with alkenyl MIDA boronates has been developed. Commercially available trans-bromo[N-succinimidyl-bis(triphenylphosphine)]palladium(II) [Pd(PPh₃)₂NBS] is an effective catalyst under the slow release conditions of MIDA boronates; with less activated alkenyl tosylates addition of the cheap, air-stable tricyclohexylphosphine tetrafluoroborate enhances reactivity.     

Synthesis of Acylborons by Ozonolysis of Alkenylboronates: Preparation of an Enantioenriched Amino Acid Acylboronate

A concise synthesis of acylborons was achieved by ozonolysis of alkenyl MIDA (N ‐methyliminodiacetic acid) boronates. This reaction exhibits excellent functional‐group tolerance and is applicable to various acyl MIDA boronates and potassium acyltrifluroborates (KATs) which could not be synthesized by previous methods. In addition, α‐amino acylborons, which would be essential for peptide ligations, were prepared for the first time. The acylboron of l ‐alanine was obtained in high enantiopurity and found to be configurationally stable. Oligopeptide synthesis between the α‐amino KATs and amino acid in dilute aqueous media was studied.     

Site‐Differentiated Polyboron Arenes Prepared by Direct C?H Borylation and Their Highly Selective Suzuki–Miyaura Cross‐Coupling Reactions

Di‐ and polyboron (hetero)arenes, site‐differentiated with MIDA boronyl (MIDA=N‐methyliminodiacetic acid) and pinacolato boronyl (Bpin), were prepared by an iridium‐catalyzed direct C H borylation of readily available (hetero)aryl MIDA boronates. The excellent synthetic uses of these multisite nucleophiles were demonstrated by the high‐yield production of a variety of multifunctionalized poly(hetero)arenes with the highly chemoselective Suzuki–Miyaura coupling (SMC) of the Bpin moiety being an essential step.     

Site‐Differentiated Polyboron Arenes Prepared by Direct C?H Borylation and Their Highly Selective Suzuki–Miyaura Cross‐Coupling Reactions

Di‐ and polyboron (hetero)arenes, site‐differentiated with MIDA boronyl (MIDA=N‐methyliminodiacetic acid) and pinacolato boronyl (Bpin), were prepared by an iridium‐catalyzed direct C H borylation of readily available (hetero)aryl MIDA boronates. The excellent synthetic uses of these multisite nucleophiles were demonstrated by the high‐yield production of a variety of multifunctionalized poly(hetero)arenes with the highly chemoselective Suzuki–Miyaura coupling (SMC) of the Bpin moiety being an essential step.     

Visible-light-promoted alkylation of unsaturated MIDA boronates using Ru(bpy)3Cl2 as the photoredox catalyst

The development of a visible light-mediated atom transfer radical addition (ATRA) of perfluoroalkyl iodides to ethynyl-, vinyl- and allyl-MIDA boronates using the reductive and oxidative quenching of [Ru(bpy)₃]Cl₂ is described. Using an operationally simple and mild protocol, the corresponding MIDA boronates containing perfluoroalkyl groups were obtained in moderate to high yields. The structures of three products were confirmed by single crystal X-ray diffraction studies.     

Regio- and Diastereoselective Synthesis of Cyclohexadienylborons via an Intermolecular Diels–Alder Reaction of Alkenyl MIDA Boronates with 2-Pyrones

An efficient synthesis of highly functionalized cyclohexadienylborons via an inverse electron-demand Diels–Alder reaction/CO₂ extrusion of alkenyl MIDA boronates with 2-pyrones is outlined. By controlling the reaction temperature, the corresponding C(sp³)-rich bicyclolactones could also be readily formed. The exo-selective reactions feature good functional-group tolerance, broad substrate scope, and excellent regio- and diastereoselectivity. Oxidation of the cyclohexadienylborons in a one-pot procedure led to the construction of aromatic boronates bearing valuable functional groups. Synthetic transformations of the C−B bond were demonstrated.     

Concise total synthesis of (-)-myxalamide A

The MIDA touch: A concise and highly convergent protecting-group-free total synthesis of (-)-myxalamide?A involves a stereoselective vinylogous Mukaiyama aldol reaction of a vinylketene silyl N,O-acetal, together with a one-pot Stille/Suzuki-Miyaura cross-coupling reaction using Burke's N-methyliminodiacetic acid (MIDA) boronate to connect left- and right-hand fragments of the molecule (see scheme).     

MIDA- and TIDA-Boronates Stabilize α-Radicals Through B−N Hyperconjugation

Multifunctional organoboron compounds increasingly enable the simple generation of complex, Csp³-rich small molecules. The ability of boron-containing functional groups to modify the reactivity of α-radicals has also enabled a myriad of chemical reactions. Boronic esters with vacant p-orbitals have a significant stabilizing effect on α-radicals due to delocalization of spin density into the empty orbital. The effect of coordinatively saturated derivatives, such as N-methyliminodiacetic acid (MIDA) boronates and counterparts, remains less clear. Herein, we demonstrate that coordinatively saturated MIDA and TIDA boronates stabilize secondary alkyl α-radicals via σ_B-N hyperconjugation in a manner that allows site-selective C−H bromination. DFT calculated radical stabilization energies and spin density maps as well as LED NMR kinetic analysis of photochemical bromination rates of different boronic esters further these findings. This work clarifies that the α-radical stabilizing effect of boronic esters does not only proceed via delocalization of radical character into vacant boron p-orbitals, but that hyperconjugation of tetrahedral boron-containing functional groups and their ligand electron delocalizing ability also play a critical role. These findings establish boron ligands as a useful dial for tuning reactivity at the α-carbon.     

Synthesis of benzylic boronates via palladium-catalyzed cross-coupling reaction of bis(pinacolato)diboron with benzylic halides

The palladium cross-coupling reaction of benzyl halides with diboron 1 yielded structurally diverse pinacol benzylic boronates. Under these reaction conditions, sensitive functionalities such as esters and nitriles are tolerated and the benzylic boronates are obtained in good to high yields.