Paul P. Lange

Carboxylates as sources of carbon nucleophiles and electrophiles: comparison of decarboxylative and decarbonylative pathways

This tutorial review provides a comparison between the concepts of catalytic decarboxylative and decarbonylative couplings for the ipso-substitution of carboxylate groups, and illustrates their potential benefits over alternative C–C bond-forming reactions. Redox-neutral decarboxylative reactions allow generating organometallic species with nucleophilic reactivity via the extrusion of carbon dioxide from metal carboxylates. Such C–C bond activating processes provide a way of employing carboxylate salts as substitutes for the traditional sources of carbon nucleophiles, i.e. stoichiometric organometallic reagents. If the decarboxylation of carboxylic acids is performed under oxidative conditions, organometallic species with electrophilic reactivity are obtained instead. These can alternatively be accessed via the extrusion of carbon monoxide from acyl–metal species generated via the oxidative addition of activated carboxylic acid derivatives (e.g. acid chlorides, anhydrides or esters) to metal complexes. In the latter two reaction types, carboxylic acids thus become substitutes for organohalides. The complementary redox-neutral and oxidative decarboxylative and decarbonylative reaction modes allow the broad use of carboxylic acids as substrates in C–C bond-forming reactions. Their applicability, scope and limitations are discussed using the examples of Heck reactions, cross-couplings and direct arylations.

Decarboxylative Cross‐Coupling of Aryl Tosylates with Aromatic Carboxylate Salts

Metal-catalyzed coupling reactions are effective synthetic tools for the formation of C C bonds between nucleophilic and electrophilic substrates at positions predefined by leaving groups. Recently, decarboxylative coupling reactions have emerged as powerful alternatives for regioselective C C bond formation, thus providing new protocols for Heck-type reactions, oxidative arylations, redox-neutral cross-coupling reactions, and allylations. The redox-neutral decarboxylative coupling reactions that have been developed in our research group aim at replacing sensitive and costly organometallic reagents, which are traditionally used as nucleophilic coupling partners, with stable, inexpensive and widely available carboxylate salts. 7] In this type of reaction, a copper(I) or silver(I) catalyst mediates the extrusion of CO2 from the carboxylates while a palladium complex catalyzes the coupling of the resulting carbon nucleophiles with carbon electrophiles (Scheme 1). In view of the high performance level of traditional crosscouplings, a widespread practical application of decarboxylative couplings hinges on a broad substrate scope, the use of inexpensive and readily available carbon electrophiles, and mild reaction conditions. The early protocols allowed the coupling of diversely functionalized ortho-substituted benzoates, heterocyclic arenecarboxylates, and a-oxocarboxylates with a wide variety of aryl and heteroaryl halides. 8,9] However, the strongly coordinating halide ions that were formed in the process were found to impede the decarboxylation of other arenecarboxylates. A decisive extension of the substrate scope covering the full range of substitution patterns including metaand para-substituted arenecarboxylates was achieved by new catalysts that allowed the use of aryl triflates as carbon electrophiles. The coupling of these substrates releases only noncoordinating anions that do not hinder the decarboxylation at the copper center. Unfortunately, the practical utility of this protocol is limited by the expense and the sensitivity of aryl triflates. The use of the inexpensive and more robust aryl ptoluenesulfonates (tosylates) is of profound interest for all types of cross-coupling reactions, and substantial effort has been devoted to the development of catalyst systems capable of activating them. In earlier protocols, nickel complexes were mostly used as catalysts, until a new class of bulky, electron-rich phosphines was discovered that strongly facilitates the oxidative addition of aryl tosylates to palladium catalysts. In recent years, aryl tosylates have successfully been employed as substrates in, for example, Stille, Suzuki, and Kumada coupling reactions, aminations, and ortho-arylations. The use of aryl tosylates as substrates in decarboxylative coupling reactions should have an even higher synthetic impact, when considering that a low coordinating ability of the leaving group is an essential prerequisite for accessing the full range of carboxylic acid substrates. We started the development of the catalyst for the desired decarboxylative cross-coupling (see Scheme in Table 1) with a series of protodecarboxylation reactions in the presence of phosphine ligands to identify phosphines that would not interfere with the decarboxylation step. Fortunately, the conversion of 3-nitrobenzoic acid into nitrobenzene using Cu2O/1,10-phenanthroline (phen) catalysts was not affected by the electron-rich, sterically demanding phosphines that are known to activate unreactive leaving groups (Scheme 2). We next investigated the performance of palladium complexes with such ligands as catalysts in the decarboxylative coupling of potassium 2-nitrobenzoate (1a) with 4-tolyl tosylate (2a) in combination with a Cu2O/phen co-catalyst (Table 1). Scheme 1. Cu/Pd-catalyzed decarboxylative cross-coupling. M = Ag, Cu; R = (hetero)aryl, vinyl, acyl; R’= (hetero)aryl; X = I, Br, Cl, OTf. Tf= trifluoromethanesulfonyl.

Silver-catalysed protodecarboxylation of carboxylic acids.

A silver-based catalyst system has been discovered that effectively promotes the protodecarboxylation of various carboxylic acids at temperatures of 80-120 degrees C--more than 50 degrees C below those of the best known copper catalysts.

Low-temperature ag/pd-catalyzed decarboxylative cross-coupling of aryl triflates with aromatic carboxylate salts.

Metal-catalyzed decarboxylative couplings are evolving into powerful synthetic tools for the regioselective formation of C C bonds. New protocols for Heck-type reactions, oxidative arylations, redox-neutral couplings, and allylations have provided innovative atom-economic and wasteminimized pathways among others to biaryls, vinyl arenes, and aryl ketones starting from readily available carboxylic acids. These transformations have reached impressive performance levels in terms of selectivity, functional group tolerance, and yield. However, their practical applicability is still somewhat limited by the high reaction temperatures currently required in the decarboxylation step. The redox-neutral decarboxylative cross-couplings developed in our group allow a regioselective C C bond formation between aryl, heteroaryl, or acyl carboxylates and aryl halides to give biaryls or aryl ketones without resorting to stoichiometric amounts of organometallic reagents. Instead, the carbon nucleophiles are generated in situ via extrusion of CO2 at a copperor silver-based decarboxylation catalyst. They are then transmetalated to the palladium catalyst, where their coupling with the aryl electrophile takes place (Scheme 1). The decarboxylation cocatalyst is vital for the conversion of most carboxylic acids. Only a few particularly reactive derivatives such as certain heteroarene2-carboxylic acids or monoalkyl oxalates can be coupled by palladium alone, presumably by a different mechanism. So far, silver-based systems have not presented advantages over copper ones in terms of reaction temperature or scope of decarboxylative cross-couplings. In contrast to copper(I), silver(I) had to be employed in overstoichiometric amounts, because a salt metathesis between the potassium carboxylates 1 and silver halides a formed within the catalytic cycle is impossible, precluding further turnover of the silver catalyst. 10] However, when reevaluating the potential of silver catalysts for protodecarboxylation reactions, we discovered conditions under which silver salts mediate the extrusion of CO2 from certain arenecarboxylates with higher efficiency than copper complexes. The new silver-based protodecarboxylation proceeds at only 120 8C—a temperature more than 50 8C below that of the best known copper catalysts. Larrosa et al. independently discovered a similar protocol. In addition, we were able to show that decarboxylative cross-couplings can be performed using aryl electrophiles with non-coordinating leaving groups such as triflates or tosylates. We reasoned that the low affinity of these ions to silver(I) might enable the crucial salt metathesis between silver sulfonate salts a and potassium carboxylates 1 (Scheme 1). This prompted us to embark on the search for a new, low-temperature protocol for the decarboxylative cross-coupling of aryl sulfonates with potassium carboxylates using a Ag/Pd catalyst system. We based the catalyst development on the model reaction of potassium 2-nitrobenzoate (1 a) with 4-chlorophenyl triflate (2 a) (see Table 1). Using a catalyst analogous to the copper-based version but employing Ag2CO3 (5 mol %) instead of Cu2O/1,10-phenanthroline, modest turnover was ob[a] Prof. Dr. L. J. Gooßen, P. P. Lange, Dr. N. Rodr guez, C. Linder FB Chemie Organische Chemie, TU Kaiserslautern Erwin-Schrçdinger-Strasse Geb. 54, 67663 Kaiserslautern (Germany) Fax: (+49) 631-205-3921 E-mail : goossen@chemie.uni-kl.de Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.200903319. Scheme 1. Ag/Pd-catalyzed decarboxylative cross-coupling. R = (hetero)aryl; R’= (hetero)aryl; X =OTf, OTs.

Biaryl and Aryl Ketone Synthesis via Pd-Catalyzed Decarboxylative Coupling of Carboxylate Salts with Aryl Triflates

A bimetallic catalyst system has been developed that for the first time allows the decarboxylative cross-coupling of aryl and acyl carboxylates with aryl triflates. In contrast to aryl halides, these electrophiles give rise to non-coordinating anions as byproducts, which do not interfere with the decarboxylation step that leads to the generation of the carbon nucleophilic cross-coupling partner. As a result, the scope of carboxylate substrates usable in this transformation was extended from ortho-substituted or otherwise activated derivatives to a broad range of ortho-, meta-, and para-substituted aromatic carboxylates. Two alternative protocols have been optimized, one involving heating the substrates in the presence of Cu(I)/1,10-phenanthroline (10-15 mol %) and PdI(2)/phosphine (2-3 mol %) in NMP for 1-24 h, the other involving Cu(I)/1,10-phenanthroline (6-15 mol %) and PdBr(2)/Tol-BINAP (2 mol %) in NMP using microwave heating for 5-10 min. While most products are accessible using standard heating, the use of microwave irradiation was found to be beneficial especially for the conversion of non-activated carboxylates with functionalized aryl triflates. The synthetic utility of the transformation is demonstrated with 48 examples showing the scope and limitations of both protocols. In mechanistic studies, the special role of microwave irradiation is elucidated, and further perspectives of decarboxylative cross-couplings are discussed.

Comparative Study of Copper‐ and Silver‐Catalyzed Protodecarboxylations of Carboxylic Acids

The protodecarboxylation of aromatic carboxylic acids by various copper and silver catalysts is investigated with the help of density functional calculations and experimental studies. The computational results reveal that the catalytic activity of copper(I)–1,10‐phenanthroline catalysts increases with the introduction of electron‐rich substituents at the phenanthroline ligand. They also predicted that for some substrates, silver complexes should possess a substantially higher decarboxylating activity than copper, which is confirmed by experimental studies, leading to the discovery of a silver(I) catalyst that effectively promotes the protodecarboxylation of various carboxylic acids at temperatures in the range of 80–120 °C—more than 50 °C below those of the best known copper(I) catalyst. The scope of the new system complements that of the copper(I)‐based method as it includes benzoates for example, with halogen or ether groups in the ortho positions.