Rolf H. Taaning

Ex Situ Generation of Stoichiometric and Substoichiometric 12CO and 13CO and Its Efficient Incorporation in Palladium Catalyzed Aminocarbonylations

A new technique for the ex situ generation of carbon monoxide (CO) and its efficient incorporation in palladium catalyzed carbonylation reactions was achieved using a simple sealed two-chamber system. The ex situ generation of CO was derived by a palladium catalyzed decarbonylation of tertiary acid chlorides using a catalyst originating from Pd(dba)(2) and P(tBu)(3). Preliminary studies using pivaloyl chloride as the CO-precursor provided an alternative approach for the aminocarbonylation of 2-pyridyl tosylate derivatives using only 1.5 equiv of CO. Further design of the acid chloride CO-precursor led to the development of a new solid, stable, and easy to handle source of CO for chemical transformations. The synthesis of this CO-precursor also provided an entry point for the late installment of an isotopically carbon-labeled acid chloride for the subsequent release of gaseous [(13)C]CO. In combination with studies aimed toward application of CO as the limiting reagent, this method provided highly efficient palladium catalyzed aminocarbonylations with CO-incorporations up to 96%. The ex situ generated CO and the two-chamber system were tested in the synthesis of several compounds of pharmaceutical interest and all of them were labeled as their [(13)C]carbonyl counterparts in good to excellent yields based on limiting CO. Finally, palladium catalyzed decarbonylation at room temperature also allowed for a successful double carbonylation. This new protocol provides a facile and clean source of gaseous CO, which is safely handled and stored. Furthermore, since the CO is generated ex situ, excellent functional group tolerance is secured in the carbonylation chamber. Finally, CO is only generated and released in minute amounts, hence, eliminating the need for specialized equipment such as CO-detectors and equipment for running high pressure reactions.

Silacarboxylic acids as efficient carbon monoxide releasing molecules: synthesis and application in palladium-catalyzed carbonylation reactions.

Silacarboxylic acids have been demonstrated to be easy to handle, air-stable carbon monoxide precursors. Different silacarboxylic acids were synthesized from the corresponding chlorosilanes and carbon dioxide, and their decarbonylation, upon treatment with an array of activators, was evaluated. The release of CO from crystalline MePh(2)SiCO(2)H proved to be highly efficient, and it was successfully applied in a selection of palladium-catalyzed carbonylative couplings using near-stoichiometric quantities of carbon monoxide precursor. Finally, the synthesis of MePh(2)Si(13)CO(2)H and its application in carbonyl labeling of two bioactive compounds was demonstrated.

Effective palladium-catalyzed hydroxycarbonylation of aryl halides with substoichiometric carbon monoxide.

A protocol for the Pd-catalyzed hydroxycarbonylation of aryl iodides, bromides, and chlorides has been developed using only 1-5 mol % of CO, corresponding to a p(CO) as low as 0.1 bar. Potassium formate is the only stoichiometric reagent, acting as a mildly basic nucleophile and a reservoir of CO. The substoichiometric CO could be delivered to the reaction from an acyl-Pd(II) precatalyst, which provides both the CO and an active catalyst, and thereby obviates the need for handling a toxic gas.

Carbonylative Heck Reactions Using CO Generated ex Situ in a Two-Chamber System

A carbonylative Heck reaction of aryl iodides and styrene derivatives employing a two-chamber system using a stable, crystalline, and nontransition metal based carbon monoxide source is reported. By applying near-stoichiometric amounts of the carbon monoxide precursor, an effective exploitation of the hazardous CO gas is obtained affording chalcone derivatives in good yields. Application to isotope labeling, incorporating (13)CO, was further established.

Palladium-catalyzed double carbonylation using near stoichiometric carbon monoxide: expedient access to substituted 13C2-labeled phenethylamines.

A novel and general approach for (13)C(2)- and (2)H-labeled phenethylamine derivatives has been developed, based on a highly convergent single-step assembly of the carbon skeleton. The efficient incorporation of two carbon-13 isotopes into phenethylamines was accomplished using a palladium-catalyzed double carbonylation of aryl iodides with near stoichiometric carbon monoxide.

Pd-catalyzed thiocarbonylation with stoichiometric carbon monoxide: scope and applications.

A general protocol for the Pd-catalyzed thiocarbonylation of aryl iodides with stoichiometric carbon monoxide has been established employing a catalytic system composed of Pd(OAc)(2) and DPEphos with low catalyst loading (1 mol %). Both electron-rich and -deficient aryl iodides proved effective for these couplings with aryl and alkyl thiols. The choice of the metal ligands and the solvent system was crucial for the efficiency and chemoselectivity of these transformations.

Palladium-Catalyzed Approach to Primary Amides Using Nongaseous Precursors

A simple protocol is reported for the preparation of primary aryl amides under Pd-catalyzed carbonylation chemistry applying a two-chamber system with crystalline and nontransition metal based sources of carbon monoxide and ammonia. The method is suitable for the synthesis of a number of primary amides with good functional group tolerance. Incorporation of (13)CO into the primary amide group was also found to be effective making this approach useful for accessing carbon isotope labeled derivatives.

Reductive Carbonylation of Aryl Halides Employing a Two-Chamber Reactor: A Protocol for the Synthesis of Aryl Aldehydes Including 13C- and D-Isotope Labeling

A protocol has been developed for conducting the palladium-catalyzed reductive carbonylation of aryl iodides and bromides using 9-methylfluorene-9-carbonyl chloride (COgen) as a source of externally delivered carbon monoxide in a sealed two-chamber system (COware), and potassium formate as the in situ hydride source. The method is tolerant to a wide number of functional groups positioned on the aromatic ring, and it can be exploited for the isotope labeling of the aldehyde group. Hence, reductive carbonylations run with (13)COgen provide a facile access to (13)C-labeled aromatic aldehydes, whereas with DCO2K, the aldehyde is specifically labeled with deuterium. Two examples of double isotopic labeling are also demonstrated. Finally, the method was applied to the specific carbon-13 labeling of the β-amyloid binding compound, florbetaben.

Access to β‐Keto Esters by Palladium‐Catalyzed Carbonylative Coupling of Aryl Halides with Monoester Potassium Malonates

Over the past 150 years since the discovery of the acetoacetic ester condensation by Geuther in 1863, and the subsequent extensive research into the reaction by Claisen, b-keto esters have played a prominent role in organic synthesis. Such compounds serve as key building blocks in the synthesis of many pharmaceuticals and natural products, providing direct access to a wide variety of heterocycles. A direct procedure for accessing b-keto esters involves the acylation of diethyl malonate, followed by partial hydrolysis and subsequent decarboxylation of only one of the two ester groups. The disadvantage of this method is the possibility of diacylation, hydrolysis of both ester groups and retro-condensation, leading to the carboxylic acid starting material. On the other hand, Wemple and co-workers reported a modified route to b-keto esters, through the acylation of monoethyl potassium malonate with acid chlorides using a combination of MgCl2 and Et3N, [6, 7] followed by decarboxylation. Nevertheless, both methods rely on the use of reactive carboxylic acid chlorides as reagents for these reactions, requiring their synthesis from the carboxylic acid precursor. An alternative and complementary approach would involve the Pd-catalyzed carbonylative a-arylation of monoethyl potassium malonate with carbon monoxide and aryl halides (Scheme 1). In this way, no reactive intermediates would be required, thus simplifying the storage of the reagents. Because of the mild reaction conditions generally associated with Pd-catalyzed couplings, a wide scope of both nucleophilic and electrophilic coupling partners would be allowed. Furthermore, this method would be ideal for the isotope labeling of the ketone group with carbon-13 and carbon-14 arising from an isotopically labeled CO, thus providing easy access to isotopically labeled heterocycles that are accessible from b-keto esters. Previously, Tanaka and Kobayashi reported a few examples of the intermolecular carbonylative arylation of malonate derivatives under high CO pressure (20 atm) and at elevated temperatures (120 8C). This method was only applied with aryl iodides, and their results were generally unpredictable in product distribution and gave variable yields. Herein, we report an effective catalytic system based on palladium, which promotes the carbonylative arylation of potassium malonate monoesters with aryl bromides, aryl triflates, and electron-deficient aryl chlorides for the mild and selective preparation of b-keto esters. Notably, the method relies on the use of only stoichiometric amounts of carbon monoxide applied from an solid precursor (COgen) and delivered ex situ, thereby allowing this approach to be highly adaptable for carbon-isotope labeling of the keto group. To identify an effective catalytic system for the carbonylative arylation of malonates, we initially examined the coupling of 4-bromobenzonitrile (1) with monoethyl potassium malonate. In a small optimization study, we quickly discovered that a combination of [Pd(dba)2] (dba = dibenzylideneacetone) and PtBu3 promoted the carbonylative coupling, allowing the isolation of b-keto ester 2 in high yield and selectivity over carboxylic acid 3 (Scheme 2). 15] Moreover, for successful coupling, this reaction required both the addition of MgCl2 (1.2 equiv) and triethylamine (4 equiv). The use of other magnesium salts, including MgBr2, MgSO4, Mg(OEt)2 and Mg(OtBu2), provided less interesting results. Exchanging MgCl2 with ZnCl2 led to a reversal in the product distribution, exclusively generating 3. Substituting the mono-

Creating carbon–carbon bonds with samarium diiodide for the synthesis of modified amino acids and peptides

In this perspective, an overview of our experiences on the application of samarium diiodide in organic synthesis for the preparation of amino acid and peptide analogues is presented. Three different carbon-carbon bond forming reactions are discussed, including side chain introductions, gamma-amino acid synthesis and acyl-like radical additions for the construction of C-C mimics of the peptidic bonds.