σ-Bond Hydroboration of Cyclopropanes

Abstract

Hydroboration of alkenes is a classical reaction in organic synthesis, in which alkenes react with boranes to give alkylboranes, with subsequent oxidation resulting in alcohols. The double bond (π-bond) of alkenes can be readily reacted with boranes owing to its high reactivity. However, the single bond (σ-bond) of alkanes has never been reacted. To pursue the development of σ-bond cleavage, we selected cyclopropanes as model substrates since they present a relatively weak σ-bond. Herein, we describe an iridium-catalyzed hydroboration of cyclopropanes, resulting in β-methyl alkylboronates. These unusually branched boronates can be derivatized by oxidation or cross-coupling chemistry, accessing "designer" products that are desired by practitioners of natural product synthesis and medicinal chemistry. Furthermore, mechanistic investigations and theoretical studies revealed the enabling role of the catalyst. Recently, several chemists including our group reported an iridium-catalyzed C-H borylation of cyclopropanes [19-21]. In one report, cyclopropanes were reacted with iridium complexes with a nitrogen bidentate ligand, 3,4,7,8-tetramethylphenanthroline (3,4,7,8-tetraMephen), which engendered a cyclopropane carbonhydrogen activation to afford borylated cyclopropanes (Fig. 1B). With the aim of achieving cyclopropane carbon-carbon activation, we forged a blueprint for selective bond activation. If an appropriate ligand were used, it might be possible to perform a "chemoselectivity switch" from C-H (intermediate A) to CC (intermediate B) bond activation in which the selectivity of CC activation could be achieved by reaction of the catalyst with the sterically less hindered Cb-Cg bond [22-24]. With these goals in mind, we conducted an extensive screening of ligands, and by using 2-[4-(1,1-dimethylethyl)-4,5-dihydro-2-oxazolyl]quinoline (t-Bu-Quinox), we achieved the first iridium-catalyzed σ-bond hydroboration of cyclopropanes (Fig. 1C). We initiated our study by finding a suitable ligand for the target reaction, consisting of N-cyclopropylpivalamide (1a) as a model mono-substituted cyclopropane. 1a was reacted with pinacolborane (H-Bpin: 1.5 equiv) in the presence of Ir dimer [Ir(OMe)(cod)]2 (5 mol%) and ligands (5 mol%) in THF at 80 ºC under nitrogen atmosphere. After an extensive screening of ligands (see Supplementary Materials), it was found that t-BuQuinox (L1) effects the cleavage of the σ-bond and forms hydroboration product 2a in 62% yield

Rhodium-catalysed selective C–C bond activation and borylation of cyclopropanes

“…Examination and optimisation of the reaction parameters were explored using CPA 1a as the substrate and pinacolborane (HBpin) as the borylating source in conjunction with various TM catalysts and ligands ( Table 1 ). As reported, 16 when the reactions were performed with 5 mol% [Ir(cod)OMe] 2 as the catalyst and 2.5 mol% t Bu-Quinox as the ligand at 130 °C for 24 h in toluene, branched boronate 3a was formed in 52% yield together with a small amount of the linear byproduct 2a ( 2a / 3a = 5/95, entry 1). In this study, we focused our attention on product 2a .…”

“…Previous computations by Yamaguchi and Yokogawa showed that the real catalyst is Ir( iii ) species when [Ir(cod)OMe] 2 and ligand t Bu-Quinox are employed. 16 As shown in Fig. 5A , our calculations indicate that the free energy of ring-opening transition state TS12 at the distal C–C bond is 2.2 kcal mol −1 lower than that of TS13 at the proximal C–C bond.…”

“…2 ). The Rh-catalysed C–H borylation proceeds first, 16 followed by C–C activation and hydrogenation (pathway I ). The Rh-catalysed C–C activation and β-H elimination generate an allylic amide, which further undergoes hydroboration (pathway II ).…”

“…Examination and optimisation of the reaction parameters were explored using CPA 1a as the substrate and pinacolborane (HBpin) as the borylating source in conjunction with various TM catalysts and ligands (Table 1). As reported, 16 when the State Key Laboratory of Coordination Chemistry, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210093, China. E-mail: shiz@nju.edu.cn; yongliang@ nju.edu.cn † Electronic supplementary information (ESI) available.…”

“…1C ). 16 Notably, this elegant chemistry exhibited excellent distal selectivity, resulting in β-methyl alkylboronates. In contrast, herein, we describe a simple and practical method to achieve hydroboration of CPAs via proximal C–C bond cleavage affording γ-amino boronates in the presence of a rhodium complex and a simple phosphine ligand ( Fig.…”