Thomas Dröge

The Measure of All Rings—N‐Heterocyclic Carbenes

Quantification and variation of characteristic properties of different ligand classes is an exciting and rewarding research field. N-Heterocyclic carbenes (NHCs) are of special interest since their electron richness and structure provide a unique class of ligands and organocatalysts. Consequently, they have found widespread application as ligands in transition-metal catalysis and organometallic chemistry, and as organocatalysts in their own right. Herein we provide an overview on physicochemical data (electronics, sterics, bond strength) of NHCs that are essential for the design, application, and mechanistic understanding of NHCs in catalysis.

Palladium‐Catalyzed Oxidative Cyclization of N‐Aryl Enamines: From Anilines to Indoles

The indole unit is one of the most abundant and relevant heterocycles in natural products and pharmaceuticals. Despite the existence of numerous methods for the synthesis and derivatization of indoles, the development of new, more efficient methods is of great importance. In this context, direct oxidative C C coupling by the selective activation of two C H bonds is a promising synthetic strategy. In contrast to established cross-coupling methods, such as the Suzuki– Miyaura coupling, prefunctionalization of the reaction centers is not required. For example, electron-rich aniline substrates can be activated and functionalized by electrophilic aromatic palladation under acidic conditions to give indolequinones or carbazoles. However, the limited scope of these reactions, the frequent requirement of a stoichiometric amount of a palladium complex, and the low yields often observed limit the usefulness of these methods. Furthermore, simple non-annulated indoles could not be prepared under these acidic conditions. Herein, we report an efficient synthesis of functionalized indoles from commercially available anilines by palladiumcatalyzed, intramolecular oxidative coupling. As this cyclization does not proceed through electrophilic aromatic palladation, a large variety of anilines can be used in this reaction. Our investigation commenced with the cyclization of methyl (Z)-3-(phenylamino)but-2-enoate (1a) to give the corresponding indole 2a. In experiments to optimize the reaction, the best results were obtained with a catalytic amount of Pd(OAc)2, Cu(OAc)2 as the oxidant, and K2CO3 as the base in DMF (Table 1, entry 1). Under these conditions, conversion was complete within 3 h at 80 8C (72% yield of the isolated product), or within less than 15 min at 140 8C, even when only 5 mol% of Pd(OAc)2 was used (not shown). Variation of the oxidant (Table 1, entries 3–6), the base (Table 1, entries 7 and 8), or the solvent (Table 1, entries 9–11) led to a decrease in the yield. The use of acetic acid as the solvent resulted in the rapid decomposition of the substrate and therefore no product formation (Table 1, entry 11). The results with Pd(TFA)2 (TFA= trifluoroacetate) were similar to those observed under the optimal conditions (Table 1, entry 12), whereas the addition of PPh3 resulted in the formation of a less active catalyst (Table 1, entry 13). Interestingly, chloride anions do not influence the reaction at all (Table 1, entry 14). A great variety of substituted anilines can be transformed into the corresponding indoles under the optimized reaction conditions (Table 2). In some cases, an increased reaction temperature (and, consequently, a shorter reaction time) led to higher yields. Substrates with a variety of electron-donating (Table 2, entries 2–8) and electron-withdrawing substituents (Table 2, entries 9–19) were converted directly into the indole products, which are versatile building blocks for subsequent synthetic modification, for example, through modern crosscoupling reactions (Table 2, entries 12–14). The ability to vary the aniline moiety so broadly is a distinct advantage of this new indole synthesis. In the case of meta-substituted substrates 1, two regioisomeric indole products 2 can be formed. Intriguingly, exclusive Table 1: Optimization of the reaction conditions.

Exploring the Oxidative Cyclization of Substituted N‐Aryl Enamines: Pd‐Catalyzed Formation of Indoles from Anilines

The direct Pd-catalyzed oxidative coupling of two C-H-bonds within N-aryl-enamines 1 allows the efficient formation of differently substituted indoles 2. In this cross-dehydrogenative coupling, many different functional groups are tolerated and the starting material N-aryl-enamines 1 can be easily prepared in one step from commercially available anilines. In addition, the whole sequence can also be run in a one-pot fashion. Optimization data, mechanistic insight, substrate scope, and applications are reported in this full paper.

Nickel-Catalyzed Cross-Coupling of Aryl Bromides with Tertiary Grignard Reagents Utilizing Donor-Functionalized N-Heterocyclic Carbenes (NHCs)

Metal-catalyzed cross-coupling reactions are among the most important transformations in organic synthesis, allowing the efficient construction of complex structures from simpler, readily available building blocks. Many applications in large and small-scale synthesis can be found in different areas such as agrochemicals, pharmaceuticals and supramolecular chemistry. Whereas the coupling of sp-hybridized carbon atoms in either reaction partner is well established, the use of C ACHTUNGTRENNUNG(sp3)-hybridized substrates presents some challenges. Catalytic cross-coupling of sterically hindered tertiary alkyl substrates is especially difficult, generally resulting in low yields, and thus, only few reports exist. A big challenge in this field is not only to get the required level of reactivity, but also to overcome competing pathways like b-hydride elimination, hydrodehalogenation or isomerization. In an early report, Kumada et al. have shown a nickelcatalyzed cross-coupling of tertiary alkyl Grignard reagents with b-bromostyrene. Cahiez et al. could obtain the same product in similar yield using an Fe catalyst, however, b-hydride elimination became competitive. Furthermore, the group of Bell used a stoichiometric amount of a copper(I) salt to alkylate pyridines and quinolines. Recently, Hintermann et al. reported an impressive selective copper-catalyzed cross-coupling of tertiary Grignard reagents of certain azacyclic electrophiles, but this protocol is limited to chloroazacycles such as pyridines, pyrimidines, quinazolines and quinoxalines (Scheme 1). A general method for the coupling of tertiary alkyl metal reagents with aryl halides would be very desirable. Due to their attractive properties N-heterocyclic carbene (NHC) ligands have found widespread applications in organometallic chemistry and transition-metal catalysis. NHCs have already been successfully applied in Kumada–Corriu– Tamao reactions. Herein we report the Kumada– Corriu–Tamao-type nickel-catalyzed cross-coupling of aryl halides with tertiary Grignard reagents. This practical advance provides selective access to highly substituted tertiary alkyl benzene derivatives, an interesting class of chemical compounds. The coupling of 4-bromobiphenyl with tBuMgCl was used as the initial model system. The high reactivity of Grignard reagents is desirable in this coupling, as is their easy accessibility. Functional group compatibility, often a problem in reactions of Grignard reagents, can be expanded, if sufficiently mild reaction conditions can be realized. Using NHC ligands, we tried to prevent the formation of undesired side products. Thus, the sterically demanding easily synthesized ligand precursor L1, IAd·HBF4, was selected for the first screening reactions. Screening of L1 together with various commercial Ni, Pd and Cu sources showed [Ni ACHTUNGTRENNUNG(acac)2] to be a uniquely suited metal precursor, with all other complexes giving lower or no catalytic activity (Table 1, entries 1 and 3). Naturally, no product was obtained in the absence of any metal source (entry 2). In addition, different solvents, bases and reaction temperatures were evaluated. The reaction can be successfully run at 0 8C, and changing the temperature to +40 or 78 8C did lower the yield significantly (entries 4 and 5). The solvent played an important role, non-coordinating solvents only afforded poor or no conversion. On the contrary, ethers, especially THF, were suitable (entries 7, 14, 16). Without an NHC ligand, the desired product could be obtained in decreased yield and selectivity after rather long reaction time (entry 8). For many other substrates this effect was even more pronounced, as became obvious upon studying the substrate scope of this reaction (see below). [a] C. Lohre, T. Drcge, Dr. C. Wang, Prof. Dr. F. Glorius Westf lische Wilhelms-Universit t M nster Organisch-Chemisches Institut, Corrensstrasse 40 48149 M nster (Germany) Fax: (+49)251-833-3202 E-mail : glorius@uni-muenster.de Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201100909. Scheme 1. Challenging cross-couplings of tertiary alkyl Grignard reagents.