Dennis U. Nielsen

Efficient Fluoride-Catalyzed Conversion of CO2 to CO at Room Temperature

A protocol for the efficient and selective reduction of carbon dioxide to carbon monoxide has been developed. Remarkably, this oxygen abstraction step can be performed with only the presence of catalytic cesium fluoride and a stoichiometric amount of a disilane in DMSO at room temperature. Rapid reduction of CO2 to CO could be achieved in only 2 h, which was observed by pressure measurements. To quantify the amount of CO produced, the reduction was coupled to an aminocarbonylation reaction using the two-chamber system, COware. The reduction was not limited to a specific disilane, since (Ph2MeSi)2 as well as (PhMe2Si)2 and (Me3Si)3SiH exhibited similar reactivity. Moreover, at a slightly elevated temperature, other fluoride salts were able to efficiently catalyze the CO2 to CO reduction. Employing a nonhygroscopic fluoride source, KHF2, omitted the need for an inert atmosphere. Substituting the disilane with silylborane, (pinacolato)BSiMe2Ph, maintained the high activity of the system, whereas the structurally related bis(pinacolato)diboron could not be activated with this fluoride methodology. Furthermore, this chemistry could be adapted to (13)C-isotope labeling of six pharmaceutically relevant compounds starting from Ba(13)CO3 in a newly developed three-chamber system.

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.

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.

Palladium catalyzed carbonylative Heck reaction affording monoprotected 1,3-ketoaldehydes.

The direct carbonylative palladium catalyzed synthesis of monoprotected 1,3-ketoaldehydes is reported starting from aryl iodides applying near stoichiometric amounts of carbon monoxide. Besides representing platforms for a variety of heterocyclic structures, these motives serve as viable precursors for the highly relevant aryl methyl ketones. The presented strategy can also be adapted for the facile and efficient incorporation of (13)C-labeled carbon monoxide.

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-

Pd-Catalyzed Carbonylative α-Arylation of Aryl Bromides: Scope and Mechanistic Studies

Reaction conditions for the three-component synthesis of aryl 1,3-diketones are reported applying the palladium-catalyzed carbonylative α-arylation of ketones with aryl bromides. The optimal conditions were found by using a catalytic system derived from [Pd(dba)2] (dba=dibenzylideneacetone) as the palladium source and 1,3-bis(diphenylphosphino)propane (DPPP) as the bidentate ligand. These transformations were run in the two-chamber reactor, COware, applying only 1.5 equivalents of carbon monoxide generated from the CO-releasing compound, 9-methylfluorene-9-carbonyl chloride (COgen). The methodology proved adaptable to a wide variety of aryl and heteroaryl bromides leading to a diverse range of aryl 1,3-diketones. A mechanistic investigation of this transformation relying on 31P and 13C NMR spectroscopy was undertaken to determine the possible catalytic pathway. Our results revealed that the combination of [Pd(dba)2] and DPPP was only reactive towards 4-bromoanisole in the presence of the sodium enolate of propiophenone suggesting that a [Pd(dppp)(enolate)] anion was initially generated before the oxidative-addition step. Subsequent CO insertion into an [Pd(Ar)(dppp)(enolate)] species provided the 1,3-diketone. These results indicate that a catalytic cycle, different from the classical carbonylation mechanism proposed by Heck, is operating. To investigate the effect of the dba ligand, the Pd0 precursor, [Pd(η3-1-PhC3H4)(η5-C5H5)], was examined. In the presence of DPPP, and in contrast to [Pd(dba)2], its oxidative addition with 4-bromoanisole occurred smoothly providing the [PdBr(Ar)(dppp)] complex. After treatment with CO, the acyl complex [Pd(CO)Br(Ar)(dppp)] was generated, however, its treatment with the sodium enolate led exclusively to the acylated enol in high yield. Nevertheless, the carbonylative α-arylation of 4-bromoanisole with either catalytic or stoichiometric [Pd(η3-1-PhC3H4)(η5-C5H5)] over a short reaction time, led to the 1,3-diketone product. Because none of the acylated enol was detected, this implied that a similar mechanistic pathway is operating as that observed for the same transformation with [Pd(dba)2] as the Pd source.

Scalable carbon dioxide electroreduction coupled to carbonylation chemistry

Significant efforts have been devoted over the last few years to develop efficient molecular electrocatalysts for the electrochemical reduction of carbon dioxide to carbon monoxide, the latter being an industrially important feedstock for the synthesis of bulk and fine chemicals. Whereas these efforts primarily focus on this formal oxygen abstraction step, there are no reports on the exploitation of the chemistry for scalable applications in carbonylation reactions. Here we describe the design and application of an inexpensive and user-friendly electrochemical set-up combined with the two-chamber technology for performing Pd-catalysed carbonylation reactions including amino- and alkoxycarbonylations, as well as carbonylative Sonogashira and Suzuki couplings with near stoichiometric carbon monoxide. The combined two-reaction process allows for milligram to gram synthesis of pharmaceutically relevant compounds. Moreover, this technology can be adapted to the use of atmospheric carbon dioxide.Electroreduction of CO2 to CO is a potential valorisation pathway of carbon dioxide for fine chemicals production. Here, the authors show a user-friendly device that couples CO2 electroreduction with carbonylation chemistry for up to gram scale synthesis of pharmaceuticals even under atmospheric CO2.

Palladium-Catalyzed Carbonylative α-Arylation of tert-Butyl Cyanoacetate with (Hetero)aryl Bromides.

A three-component coupling protocol has been developed for the generation of 3-oxo-3-(hetero)arylpropanenitriles via a carbonylative palladium-catalyzed α-arylation of tert-butyl 2-cyanoacetates with (hetero)aryl bromides followed by an acid-mediated decarboxylation step. Through the combination of only a stoichiometric loading of carbon monoxide and mild basic reaction conditions such as MgCl2 and dicyclohexylmethylamine for the deprotonation step, an excellent functional group tolerance was ensured for the methodology. Through the use of (13)C-labeled carbon monoxide generated from (13)COgen, the corresponding (13)C-isotopically labeled β-ketonitriles were obtained, and these products could subsequently be converted into cyanoalkynes and 3-cyanobenzofurans with site specific (13)C-isotope labeling.

Efficient Water Reduction with sp3-sp3 Diboron(4) Compounds: Application to Hydrogenations, H–D Exchange Reactions, and Carbonyl Reductions

A series of crystalline sp3 -sp3 diboron(4) compounds were synthesized and shown to promote the facile reduction of water with dihydrogen formation. The application of these diborons as simple and effective dihydrogen and dideuterium sources was demonstrated by conducting a series of selective reductions of alkynes and alkenes, and hydrogen-deuterium exchange reactions using two-chamber reactors. Finally, as the water reduction reaction generates an intermediate borohydride species, a range of aldehydes and ketones were reduced by using water as the hydride source.

Chemically and electrochemically catalysed conversion of CO 2 to CO with follow-up utilization to value-added chemicals

AbstractCarbon dioxide is ubiquitous and a vital molecule for maintaining life on our planet. However, the ever-increasing emission of anthropogenic CO2 into our atmosphere has provoked dramatic climate changes. In principle, CO2 could represent an important one-carbon building block for the chemical industry, yet its high thermodynamic and kinetic stability has limited its applicability to only a handful of industrial applications. On the other hand, carbon monoxide represents a more versatile reagent applied in many industrial transformations. Here we review the different methods for converting CO2 to CO with specific focus on the reverse water gas shift reaction, main element reductants, and electrochemical protocols applying homogeneous and heterogeneous catalysts. Particular emphasis is given to synthetic methods that couple the deoxygenation step with a follow-up carbonylation step for the synthesis of carbonyl-containing molecules, thus avoiding the need to handle or store this toxic but highly synthetically useful diatomic gas.CO is a vital building block in organic synthesis but, due to its toxicity, storage and transport can be problematic. This review focuses on the methods — both chemical and electrochemical — for the in situ generation of CO from CO2, and its subsequent incorporation into chemicals through catalytic means.