Exploiting the Bis-Nucleophilicity of α-Aminoboronates: Copper-Catalyzed, Intramolecular Aminoalkylations of Bromobenzoyl Chlorides

Abstract

α-Aminoboronate salts are interesting examples of heteroatomic species containing adjacent nucleophilic centers. We have developed an acylation/arylation reaction using 2-bromobenzoyl chlorides as bis-electrophiles that harnesses the nucleophilicity of both positions, leading to isoindolinones. The reactions proceed under mild conditions via an intramolecular, Cu-catalyzed sp(3)-sp(2) coupling, giving products in up to 95% yield. These conditions enable arylation of α,α-disubstituted aminoboronates, which are difficult to accomplish using methods based on less abundant and more expensive transition metals.

Stereoinvertive C–C Bond Formation at the Boron‐Bound Stereogenic Centers through Copper‐Bipyridine‐Catalyzed Intramolecular Coupling of α‐Aminobenzylboronic Esters

“…(Scheme ). The isoindolinone product was obtained quantitatively, but in an almost racemic form (1 % ee ), as indicated in the previous report . 4,4′‐Disubstituted bipyridines L2 and L3 gave the product in good yield, but with low enantiospecificity.…”

“…A possible reaction mechanism is proposed on the basis of the report by Dumas et al (Scheme 6). [12,18] Our observation of stereochemical inversion strongly suggests that the transmetalation is reasonably explained by attack by electrophilic copper(I) species from the backside of the boron atom at the stereogenic carbon atom. This backside attack is preferred by the steric congestion at the frontside because of intramolecular coordination of the amide carbonyl to the boron atom.…”

“…During the course of our study of the stereospecific cross‐coupling of α‐aminoalkylboronic acid derivatives, a report from the Dumas group caught our attention: α‐[( o ‐bromobenzoyl)amino]benzylboronates undergo intramolecular cross‐coupling to form 3‐arylisoindolinones in the presence of a 2,2′‐bipyridine/copper(II) catalyst (Figure b) . This intramolecular reaction appears to highly valuable synthetically because, even though it is a simple cyclization, the substrates can be synthesized through the coupling of two easily available components, that is, α‐aminoalkylboronic acids and o ‐haloaroyl chlorides, through an amidation reaction.…”

“…To our knowledge, there has been no precedent for stereospecific cross-coupling at fully substituted metal-bound stereogenic carbons to date.During the course of our study of the stereospecific crosscoupling of a-aminoalkylboronic acid derivatives, [7b,d,h] a report from the Dumas group caught our attention: a-[(obromobenzoyl)amino]benzylboronates undergo intramolecular cross-coupling to form 3-arylisoindolinones in the presence of a 2,2'-bipyridine/copper(II) catalyst (Figure 1 b). [12] This intramolecular reaction appears to highly valuable synthetically because, even though it is a simple cyclization, the substrates can be synthesized through the coupling of two easily available components, that is, a-aminoalkylboronic acids and o-haloaroyl chlorides, through an amidation reaction. Although the report claimed that complete racemization was observed in a reaction of enantiopure a-[(o-bromobenzoyl)amino]benzylboronates under standard reaction conditions, we decided to examine this potentially useful synthetic transformation in more detail.…”

“…The isoindolinone product was obtained quantitatively, but in an almost racemic form (1 % ee), as indicated in the previous report. [12] 4,4'-Disubstituted bipyridines L2 and L3 gave the product in good yield, but with low enantiospecificity. By contrast, 6,6'-disubstituted bipyridines bearing t-butyl (L4) and phenyl (L5) groups at both the 6-and 6'-positions gave almost no desired product, but gave the protodeborylation product in high yields.…”