Nuria Rodríguez

Carboxylic Acids as Substrates in Homogeneous Catalysis

In organic molecules carboxylic acid groups are among the most common functionalities. Activated derivatives of carboxylic acids have long served as versatile connection points in derivatizations and in the construction of carbon frameworks. In more recent years numerous catalytic transformations have been discovered which have made it possible for carboxylic acids to be used as building blocks without the need for additional activation steps. A large number of different product classes have become accessible from this single functionality along multifaceted reaction pathways. The frontispiece illustrates an important reason for this: In the catalytic cycles carbon monoxide gas can be released from acyl metal complexes, and gaseous carbon dioxide from carboxylate complexes, with different organometallic species being formed in each case. Thus, carboxylic acids can be used as synthetic equivalents of acyl, aryl, or alkyl halides, as well as organometallic reagents. This review provides an overview of interesting catalytic transformations of carboxylic acids and a number of derivatives accessible from them in situ. It serves to provide an invitation to complement, refine, and use these new methods in organic synthesis.

Decarboxylative Biaryl Synthesis from Aromatic Carboxylates and Aryl Triflates

A new catalyst system, generated in situ from Cu2O, 1,10-phenanthroline, PdI2, and Tol-BINAP, for the first time allows the decarboxylative coupling of carboxylic acids with aryl triflates. In contrast to previous decarboxylative couplings that remained limited to certain activated carboxylates, e.g., ortho-substituted benzoates, this halide-free protocol is generally applicable to aromatic carboxylic acid salts regardless of their substitution pattern.

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.

Palladium-catalyzed N-(2-pyridyl)sulfonyl-directed C(sp3)–H γ-arylation of amino acid derivatives

The direct Pd-catalyzed γ-arylation of amino acid esters bearing a removable N-(2-pyridyl)sulfonyl directing group is described. A variety of N-(2-pyridyl)sulfonamide amino acid derivatives, including α-quaternary amino acid and β-amino acid substrates, react with iodoarenes in the presence of Pd(OAc)2 to provide γ-arylated products in synthetically useful yields. An unprecedented remote C(sp3)–H arylation of dipeptides is presented, illustrating the compatibility of the method with the presence of the peptidic bond. The process occurs without racemization at the Cα center and the auxiliary controlling group can be easily installed and removed in the amino acid backbone. A bimetallic PdII γ-metalated complex has been isolated and characterized showing the key role exerted by the (2-pyridyl)sulfonyl unit.

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.

New catalytic transformations of carboxylic acids

A series of metal-catalyzed processes are presented, in which carboxylic acids act as sources of either carbon nucleophiles or electrophiles, depending on the catalyst employed, the mode of activation, and the reaction conditions. A first reaction mode is the addition of carboxylic acids or amides over C-C multiple bonds, giving rise to enol esters or enamides, respectively. The challenge here is to control both the regio- and stereoselectivity of these reactions by the choice of the catalyst system. Alternatively, carboxylic acids can efficiently be decarboxylated using new Cu catalysts to give aryl-metal intermediates. Under protic conditions, these carbon nucleophiles give the corresponding arenes. If carboxylate salts are employed instead of the free acids, the aryl-metal species resulting from the catalytic decarboxylation can be utilized for the synthesis of biaryls in a novel cross-coupling reaction with aryl halides, thus replacing stoichiometric organometallic reagents. An activation with coupling reagents or simple conversion to esters allows the oxidative addition of carboxylic acids to transition-metal catalysts under formation of acyl-metal species, which can either be reduced to aldehydes, or coupled with nucleophiles. At elevated temperatures, such acyl-metal species decarbonylate, so that carboxylic acids become synthetic equivalents for aryl or alkyl halides, e.g., in Heck reactions.

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.

Microwave-Assisted Cu-Catalyzed Protodecarboxylation of Aromatic Carboxylic Acids

An effective protocol has been developed that allows the smooth protodecarboxylation of diversely functionalized aromatic carboxylic acids within 5-15 min. In the presence of at most 5 mol % of an inexpensive catalyst generated in situ from copper(I) oxide and 1,10-phenanthroline, even nonactivated benzoates were converted in high yields and with great preparative ease.

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.