Arkaitz Correa

Palladium-Catalyzed Direct Carboxylation of Aryl Bromides with Carbon Dioxide

A novel protocol for the direct carbon dioxide insertion (CO(2)) into aryl halides in a catalytic manner is presented herein. Unlike other carboxylation methods using CO(2), there is no need for the synthesis of the corresponding organometallic intermediates. Additionally, and in contrast to the well-established carbonylation processes, our protocol does not use highly toxic CO for the preparation of benzoic acids. Furthermore, this method is distinguished by its mild conditions, allowing the tolerance of a wide range of functional groups and substitution patterns. The crucial step of the process involves a challenging catalytic CO(2) insertion into Pd-C bonds.

Copper‐Catalyzed Cross‐Couplings with Part‐per‐Million Catalyst Loadings

Due to the importance of functionalized arenes as scaffolds in applied organic materials and biologically relevant molecules, metal-catalyzed cross-couplings have gained significant attention in recent years. 2] Among them Ullmann type C X bond formations are particularly attractive because they often allow the use of low-cost starting materials in combination with readily available copper salts. Whereas the initial protocols required high temperatures and over-stoichiometric quantities of metal, recent approaches involving wellchosen and optimized metal–ligand combinations allow for milder reaction conditions and catalytic turnover. Despite these significant advances it has to be noted that commonly in these catalytic Ullmann type reactions both TONs (turnover numbers) as well as TOFs (turnover frequencies) remain rather limited resulting in the requirement of metal salt amounts in the range of 5 to 10 mol%. Lowering the catalyst loading leads to extended reaction times and decreased product yields. Here, we report on Ullmann type reactions with “homeopathic amounts” of copper salts. During investigations of iron-catalyzed cross-coupling reactions 8] it was noted that for some substrate combinations the catalyst activity depended on the metal salt source and its purity. Those observations suggested a closer look into the effects of metal traces under the applied reaction conditions. Taking into account the results by Taillefer and others on Fe/Cu co-catalyses, copper became the prime metal of choice. To our surprise we found that even with catalyst loadings in the 0.01 mol% range of copper(II) salts N-, O-, and S-arylations were possible to provide the corresponding products in yields > 90%. As a representative example, the coupling between pyrazole (1) and phenyliodide (2, 1.5 equiv) to provide N-arylated product 3 [Eq. (1)] was studied in detail. Further reaction components were N,N’dimethylethylenediamine (DMEDA) as (potential) ligand (20 mol %), K3PO4·H2O as base (2 equiv) [12] and toluene as solvent. The reaction mixture was kept under inert atmosphere at 135 8C in a sealed microwave tube for 24 h.

Ni-Catalyzed Direct Carboxylation of Benzyl Halides with CO2

A novel Ni-catalyzed carboxylation of benzyl halides with CO(2) has been developed. The described carboxylation reaction proceeds under mild conditions (atmospheric CO(2) pressure) at room temperature. Unlike other routes for similar means, our method does not require well-defined and sensitive organometallic reagents and thus is a user-friendly and operationally simple protocol for assembling phenylacetic acids.

Ni-Catalyzed Carboxylation of C(sp2)– and C(sp3)–O Bonds with CO2

In recent years a significant progress has been made for the carboxylation of aryl and benzyl halides with CO2, becoming convenient alternatives to the use of stoichiometric amounts of well-defined metal species. Still, however, most of these processes require the use of pyrophoric and air-sensitive reagents and the current methods are mostly restricted to organic halides. Therefore, the discovery of a mild, operationally simple alternate carboxylation that occurs with a wide substrate scope employing readily available coupling partners will be highly desirable. Herein, we report a new protocol that deals with the development of a synergistic activation of CO2 and a rather challenging activation of inert C(sp(2))-O and C(sp(3))-O bonds derived from simple and cheap alcohols, a previously unrecognized opportunity in this field. This unprecedented carboxylation event is characterized by its simplicity, mild reaction conditions, remarkable selectivity pattern and an excellent chemoselectivity profile using air-, moisture-insensitive and easy-to-handle nickel precatalysts. Our results render our method a powerful alternative, practicality and novelty aside, to commonly used organic halides as counterparts in carboxylation protocols. Furthermore, this study shows, for the first time, that traceless directing groups allow for the reductive coupling of substrates without extended π-systems, a typical requisite in many C-O bond-cleavage reactions. Taking into consideration the limited knowledge in catalytic carboxylative reductive events, and the prospective impact of providing a new tool for accessing valuable carboxylic acids, we believe this work opens up new vistas and allows new tactics in reductive coupling events.

Metal-Catalyzed Reductive Coupling Reactions of Organic Halides with Carbonyl-Type Compounds

Metal-catalyzed reductive coupling reactions of aryl halides and (pseudo)halides with carbonyl-type compounds have undergone an impressive development within the last years. These methodologies have shown to be a powerful alternate strategy, practicality aside, to the use of stoichiometric, well-defined, and, in some cases, air-sensitive organometallic species. In this Minireview, the recent findings in this field are summarized, with particular emphasis on the mechanistic interpretation of the results and future aspects of this area of expertise.

Synergistic Palladium-Catalyzed C(sp3)H Activation/C(sp3)O Bond Formation: A Direct, Step-Economical Route to Benzolactones†

In the last decade, C H bond-activation protocols have profoundly changed the landscape of organic synthesis through unconventional bond-disconnection strategies for the assembly of complex organic molecules. Ideally, directing groups that are commonly employed in C H activation processes should have a dual role by assisting chelation and subsequently promoting further functionalization. The use of benzoic acids holds great promise in this regard, as illustrated by the recent work of Yu and co-workers, and other research groups. Despite the available background knowledge, the development of catalytic methods for activating C(sp) H bonds is still in its infancy. Indeed, it is highly desirable to design new synthetic pathways based on C(sp) H activation in order to dramatically increase molecular complexity while avoiding tedious functional group manipulation. Benzolactones are a prominent structural motif of many bioactive natural products and pharmaceutically important compounds. Classical methods for the synthesis of benzolactones include the cyclization of hydroxy acids or halolactonization processes (Scheme 1, path b). Unfortunately, these methods require prefunctionalization steps, which limit the applicability because of the need for additional synthetic steps (Scheme 1, path a). The most attractive route toward benzolactones 2 would imply a direct catalytic conversion of benzoic acids 1, thus drastically reducing the overall number of synthetic steps (Scheme 1, path c). Despite encouraging precedents, particularly the pioneering and elegant work reported by Sames and co-workers when using Pt catalysts, this seemingly routine transformation is not yet efficient because of the low functional group tolerance, the high price of Pt, and the limited substitution patterns that can be accessed, thus enforcing a change in strategy. As part of our ongoing interest in the synthesis of benzoic acids by Pdcatalyzed CO2 activation, [11] it was anticipated that 1 might undergo a Pd-catalyzed activation of a proximal C(sp) H bond, followed by a virtually unexplored reductive elimination of a Pd intermediate to form a C(sp) O bond (Scheme 1, path c). This step would be rather challenging because of the large energy gap between the highest occupied molecular orbital (HOMO) of the Pd O bond and the lowest unoccupied molecular orbital (LUMO) of the Pd C bond, and the substantial ionic character of the Pd O bond. Overall, path c (Scheme 1) would constitute a direct, stepeconomical approach toward benzolactones 2. We hypothesized that the judicious choice of a supporting ligand and its appropriate fine-tuning might play an important, if not critical, role in the synthesis of 2. Herein, we demonstrate that these two mechanistically distinct Pd-catalyzed processes can be drastically accelerated by the employment of an Nprotected amino acid as the supporting ligand in the synthesis of highly functionalized benzolactones with a diverse set of substitution patterns that are beyond reach otherwise. We began our study with 1a as the model substrate. After considerable optimization, we found that the use of Pd(OAc)2, K2HPO4, and Ag2CO3 as the oxidant in chlorobenzene as the solvent afforded a remarkable level of activity (Table 1). As expected from our previous work in inert-bond activation, a minor modification in the ligand backbone had a detrimental impact on the reaction outcome. Among the ligands examined, we noticed that the use of L2 and L3 was highly beneficial (Table 1, entries 2–3). Subsequently, we found that commercially available N-protected amino acids L4–L9 could be successfully employed as ligands (Table 1, entries 4–10). The beneficial effect of using Nprotected amino acids for the activation of various C(sp) H bonds has already been demonstrated by the pioneering work of Yu and co-workers; however, the use of N-protected amino acids for the functionalization of C(sp) H bonds has received much less attention. To the best of our knowledge, N-protected amino acids have not been employed as ligands in Pd-catalyzed C(sp) O bond-forming reactions. Ligand L7 was particularly active; its use drastically reduced the yield of 3a while the yield of 2a was increased up to 95% (Table 1, Scheme 1. Synthetic approaches to benzolactones.

Iron-Catalyzed N-Arylations of Amides

Transition metal-catalyzed N-arylation of amides constitutes a powerful C N bond-forming process that has been extensively utilized in pharmaceutical and medicinal chemistry. Despite remarkable advances in both palladiumand copper-catalyzed reactions of this type, the development of alternative catalysts involving more cost-efficient, nontoxic, and environmentally friendly metals to effect the target process remains an issue of scientific interest and para ACHTUNGTRENNUNGmount industrial significance. In this respect, iron poses as an ideal metal that offers significant advantages considering its low cost, ready availability, and environmentally benign character. Although iron-catalyzed C C cross-coupling reactions have attracted particular attention, the application of iron salts for the challenging carbon–heteroatom bond formation has remained largely undeveloped. Only recently, we found highly practical iron catalysts for the formation of C N, C O, and C S linkages by means of arylation of nitrogen, oxygen, and sulfur nucleophiles, respectively, with aryl halides. In connection with this work, we present herein a versatile, convenient, and experimentally simple iron-catalyzed N-arylation of primary amides (including aromatic, heterocyclic, and aliphatic substrates) and demonstrate its applicability to the synthesis of valuable N-heterocycles by intramolecular ring closures. The key components for the presented catalyst system were 10 mol% of easy-to-handle FeCl3 and 20 mol% of inexpensive N,N’-dimethylethylenediamine (DMEDA). In our initial studies, we obtained promising results in conversions of amides, which encouraged us to investigate the scope of this synthetically valuable transformation. The couplings of differently substituted primary amides with phenyl iodide under the previously optimized conditions proceeded in moderate to excellent yields (43–96%; Table 1). Screening studies revealed that the choice of the base and the solvent played a determining role. Thus, in most cases the use of K2CO3 led to higher yields than K3PO4 or NaOtBu, and the employment of toluene as solvent at 135 8C proved to be crucial for the success of the reaction. Benzamides bearing electron-donating substituents (entries 3 and 4, Table 1) afforded better results than those having electron-withdrawing groups (entry 2, Table 1). Also aliphatic amides provided the arylated products in moderate to good yields (entries 6– 8, Table 1), with the exception of formamide (entry 5, Table 1), which was almost unreactive. Gratifyingly, important heterocyclic amides such as those bearing pyridinyl (entry 9, Table 1) and thiophenyl (entry 10, Table 1) moieties underwent coupling reactions providing the products in moderate to good yields under standard conditions. Conversely, secondary amides such as N-methylbenzamide and N-benzylbenzamide gave the corresponding N-arylated products in only trace amounts. To determine the applicability of the iron-catalyzed Narylation with respect to the aryl halides, the substrate scope

Ni-Catalyzed Direct Reductive Amidation via C–O Bond Cleavage

A novel Ni-catalyzed reductive amidation of C(sp(2))-O and C(sp(3))-O electrophiles with isocyanates is described. This umpolung reaction allows for an unconventional preparation of benzamides using simple starting materials and easy-to-handle Ni catalysts.

Pd-catalyzed intramolecular acylation of aryl bromides via C-H functionalization: a highly efficient synthesis of benzocyclobutenones.

A new catalyst system for the intramolecular acylation of aldehydes with aryl bromides via C-H functionalization is described. The transformation is distinguished by a remarkable functional group tolerance and hence allows for the synthesis of a wide variety of highly functionalized benzocyclobutenones with a diverse set of substitution patterns from simple and easily accessible precursors.

Nickel‐Catalyzed Decarbonylative CH Coupling Reactions: A Strategy for Preparing Bis(heteroaryl) Backbones

therequirement for stoichiometric amounts of silver- or copper-based oxidants does not make these protocols attractiveenough from a pharmaceutical point of view. Therefore, thedevelopment of new catalytic protocols that can face all thesechallenges,whilereadilygivingaccesstobis(heteroaryl)coreswith a diverse set of substituents would be a highly desirablegoal in organic synthesis.Prompted by the pioneering decarboxylative arylationprocesses described by Goossen et al. in 2006,