Dedicated to Professor Peter Stanetty on the occasion of his 60th birthdayThe selective functionalization of aryl and heteroaryl compounds is an important synthetic task. The resulting polyfunctional (hetero)aryl derivatives are often essential building blocks in the synthesis of pharmaceuticals, agrochemicals, and new organic materials.[1] We envisaged that bimetallic [2] aromatic derivatives of type 1, which bear two metal-centered substituents of distinctly different reactivity, would be useful reagents. Their stepwise reaction with two electrophiles E 1 and E 2 would provide products of type 2 and 3 (Scheme 1).Unfortunately, the reaction of para-iodoboronic ester 4 a [3] with iPrMgCl afforded only the corresponding isopropylboronate, which results from the attack of the Grignard reagent at the boronic ester functionality. However, the reaction with the new reagent iPrMgCl·LiCl [4] (À78 8C, 2 h) furnished the desired magnesiated boronic ester 5 a, which reacted with a variety of electrophiles to provide boronic esters of type 6 in good yields (Scheme 2, Table 1). Thus, the reaction of 5 a with allylic bromides in the presence of a catalytic amount of CuCN·2 LiCl [5] furnished the expected allylated boronic esters 6 a and 6 b in 77 and 67 % yield, respectively (Table 1, entries 1 and 2). Acylation reactions proceeded best when the Grignard reagents 5 a and 5 b were transmetalated stoichiometrically with CuCN·2 LiCl. Both aliphatic and aromatic acid chlorides reacted smoothly to give the keto-substituted boronic esters 6 c, 6 d, and 6 i in 72, 73, and 71 % yield, respectively (Table 1, entries 3, 4, and 9). The magnesiated boronic esters 5 a-b also added directly to benzaldehyde to provide the hydroxy-substituted boronic esters 6 e and 6 h in 83 and 71 % yield, respectively (Table 1, entries 5 and 8). The boronic ester cuprates underwent a smooth addition-elimination reaction with 3-iodocyclohexenones to furnish the expected b-substituted unsaturated ketones 6 f (78 %), 6 g (79 %), and 6 j (76 %; Table 1, entries 6, 7, and 10). Preliminary experiments showed that the ortho-magnesiated phenylboronic ester 5 c displayed a lower reactivity towards electrophiles. However, its allylation gave the boronic ester 6 k in 71 % yield (Table 1, entry 11).By using the readily available heterocyclic diiodides 7, [6] 8, [7] and 9, [8] it was possible to prepare the iodoheteroaryl boronic esters 11 (76 %), 12 (76 %), and 13 (81 %) by an I/Mg exchange followed by treatment with the dioxaborolane 10 (Scheme 3). These boronic esters were readily converted by treatment with iPrMgCl·LiCl at À78 8C into the related magnesiated species 14-16, which reacted with various electrophiles as found for the magnesiated carbocyclic boronic esters. Thus, the copper(i)-catalyzed allylation of 14 and 16 provided the allylated heterocyclic boronic esters 17 a and 17 c in 83 and 91 % yield, respectively (Table 2, entries 1 and 3). Transmetalation of the magnesiated 2-indolyl boronic ester 15 with CuCN·2 LiCl, followed by treatment with Scheme 1....

The direct magnesiation of highly functionalized aromatics bearing an ester, a nitrile, or a ketone can be readily performed by using an OBoc as a directing group and TMPMgCl.LiCl as a base. It allows, for example, the preparation of a meta-magnesiated benzophenone in >95%. After quenching, highly functionalized and substituted benzenes are obtained. [reaction: see text].

Professor Peter Stanetty zum 60. Geburtstag gewidmet Die selektive Funktionalisierung von Aryl-und Heteroarylverbindungen ist eine wichtige präparative Aufgabe. Die resultierenden polyfunktionellen (Hetero-)Arylderivate sind oft essenzielle Bausteine von Pharmazeutika, Agrochemikalien und neuen organischen Materialien.[1] Unser Ziel war die Entwicklung bimetallischer [2] [5] die erwarteten allylierten Boronsäureester 6 a und 6 b in 77 bzw. 67 % Ausbeute (Nr. 1 und 2 in Tabelle 1). Acylierungen wurden am effizientesten bei stöchiometrischer Transmetallierung der GrignardReagentien 5 a und 5 b mit CuCN·2 LiCl durchgeführt. Aliphatische und aromatische Säurechloride reagierten glatt zu den Oxo-substituierten Boronsäureestern 6 c, 6 d und 6 i (72, 73 bzw. 71 %; Nr. 3, 4 und 9). Die magnesierten Boronsäu-reester 5 a-b addierten ebenfalls direkt an Benzaldehyd zu den Hydroxy-substituierten Boronsäureestern 6 e und 6 h in 83 % bzw. 71 % Ausbeute (Nr. 5 und 8). Die cuprierten Boronsäureester gingen leicht Additions-Eliminierungs-Reaktionen mit 3-Iodcyclohexenonen zu den erwarteten bsubstituierten ungesättigten Ketonen 6 f, 6 g und 6 j (78, 79 bzw. 76 %; Nr. 6,7 und 10) ein. Erste Experimente mit dem ortho-magnesierten Phenylboronsäureester 5 c zeigten, dass dieser eine geringere Reaktivität gegen Elektrophile aufwies; allerdings gelang seine Allylierung zum Boronsäureester 6 k in 71 % Ausbeute (Nr. 11).Unter Verwendung von leicht zugänglichen heterocyclischen Diiodiden wie 7, [6] Schema 3. Synthese der Iod-substituierten heterocyclischen Boronsäureester 11-13 über Iod-Magnesium-Austausch. Ts = para-Toluolsulfonyl.

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Methicillin-resistant Staphylococcus aureus (MRSA) causes severe infections with only few effective antibiotic therapies currently available. To approach this challenge, chemical entities with a novel and resistance-free mode of action are desperately needed. Here, we introduce a new hydroxyamide compound that effectively reduces the expression of devastating toxins in various S. aureus and MRSA strains. The molecular mechanism was investigated by transcriptome analysis as well as by affinity-based protein profiling. Down-regulation of several pathogenesis associated genes suggested the inhibition of a central virulence-related pathway. Mass spectrometry-based chemical proteomics revealed putative molecular targets. Systemic treatment with the hydroxyamide showed significant reduction of abscess sizes in a MRSA mouse skin infection model. The absence of resistance development in vitro further underlines the finding that targeting virulence could lead to prolonged therapeutic options in comparison to antibiotics that directly address bacterial survival.