Oxalyl Boronates Enable Modular Synthesis of Bioactive Imidazoles.

Described herein is the preparation of oxalyl boronate building blocks and their application for the construction of heterocycles. The oxalyl unit, readily accessible through commercially available starting materials, enables a modular approach for the synthesis of imidazoles. A variety of aromatic, heteroaromatic, and alkyl carboxaldehydes were condensed with oxalyl boronates to afford substituted boryl imidazoles in a regiocontrolled fashion. Subsequent palladium-catalyzed cross-coupling with haloarenes furnished the desired trisubstituted imidazole scaffolds. To demonstrate the utility of these scaffolds, potent inhibitors of the serine/threonine-protein kinase STK10 were synthesized.

Boron-containing enamine and enamide linchpins in the synthesis of nitrogen heterocycles.

The use of α-boryl enamine and enamide linchpins in the synthesis of nitrogen heterocycles has been demonstrated. Boryl enamines provide ready access to the corresponding α-halo aldehydes, which undergo regioselective annulation to form borylated thiazoles. A condensation/amidation sequence converts α-boryl aldehydes into stable α-boryl enamides without concomitant C → N migration. We also show that palladium-catalyzed cyclization of α-boryl enamides leads to synthetically versatile isoindolones. These molecules can be subsequently used to access polycyclic scaffolds.

Author Correction: Amine hemilability enables boron to mechanistically resemble either hydride or proton.

During the revision of this Article prior to publication, a computational study was reported (Vallejos, M. M. & Pellegrinet, S. C. Theoretical study of the BF3-promoted rearrangement of oxiranyl N-methyliminodiacetic acid boronates. J. Org. Chem. 82, 5917-5925; 2017) that evaluates the nucleophilic boryl transfer mechanism predicted in this Article; this reference has now been added as number 19, and the subsequent references renumbered.

Amine hemilability enables boron to mechanistically resemble either hydride or proton.

Tetracoordinate MIDA (N-methyliminodiacetic acid) boronates have found broad utility in chemical synthesis. Here, we describe mechanistic insights into the migratory aptitude of the MIDA boryl group in boron transfer processes, and show that the hemilability of the nitrogen atom on the MIDA ligand enables boron to mechanistically resemble either a hydride or a proton. The first case involves a 1,2-boryl shift, in which boron migrates as a nucleophile in its tetracoordinate form. The second case involves a neighbouring atom-promoted 1,4-boryl shift, in which boron migrates as an electrophile in its pseudo-tricoordinate form. Density functional theory studies and in situ NMR measurements all suggest that MIDA can act as a dynamic switch. These findings encouraged the development of novel migration processes involving boron that exploit the chameleonic behaviour of boron by acting as both a nucleophile and an electrophile, including the first report of a compound with a boronate functionality bound to carbon in the carboxylic acid oxidation state.

Access to Cyclic Amino Boronates via Rhodium-Catalyzed Functionalization of Alkyl MIDA Boronates.

Herein, we describe the rhodium-catalyzed C-H amination reaction of 1,2-boryl sulfamate esters derived from amphoteric α-boryl aldehydes. Depending on the substitution pattern of the boryl sulfamate ester, a diverse range of five- or six-membered ring heterocycles are accessible using this transformation. The highly chemoselective nature of the C-H functionalization reaction preserves the alkyl boronate functional group, which enables the synthesis of B-C-N and B-C-C-N motifs that are present in a number of hydrolase inhibitors.

Condensation-Driven Assembly of Boron-Containing Bis(Heteroaryl) Motifs Using a Linchpin Approach.

Herein, we describe the bromomethyl acyl boronate linchpin--an enabling reagent for the condensation-driven assembly of novel bis(heteroaryl) motifs. This building block is readily accessible from commercially available starting materials. A variety of 2-amino- and 2-methylpyridines were reacted with MIDA-protected bromomethyl acylboronate to afford 2-boryl imidazo[1,2-a]pyridine and 2-boryl indolizine derivatives, respectively, in excellent yields. Subsequent condensation with hydroxyamidines and hydrazonamides converted the intermediate heterocycles into novel boron-containing bis(heteroaryl) units characterized by high thermal stability.

Development of the direct Suzuki-Miyaura cross-coupling of primary B-alkyl MIDA-boronates and aryl bromides.

The development of a palladium-catalyzed sp(3)-sp(2) Suzuki-Miyaura cross-coupling of B-alkyl-N-methyliminodiacetyl (B-alkyl MIDA) boronates and (hetero)aryl bromides is reported. This transformation is tolerant of a variety of functional groups (F, NO2, CN, Cl, COCH3, and CHO). B-Alkyl MIDA boronates allow an efficient cross-coupling reaction directed toward the synthesis of unsymmetrical methylene diaryls as well as alkylated arenes in good to excellent yields.