Giancarlo Franciò

Highly efficient enantioselective catalysis in supercritical carbon dioxide using the perfluoroalkyl-substituted ligand (R,S)-3-H2F6-BINAPHOS

Abstract Perfluoroalkyl-substitution of the aryl groups in the BINAPHOS skeleton was achieved using a synthetic strategy based on the Cu(I)-catalyzed cross coupling of arylmagnesium bromide and F(CF 2 ) 6 (CH 2 ) 2 I. The rhodium complexes of the new ligand ( R , S )-3-H 2 F 6 –BINAPHOS ( 10 ) exhibited spectroscopic properties and reactivities similar to those of the unsubstituted parent compounds. The substitution provided a high affinity of the ligand and its complexes for scCO 2 allowing the development of ecologically benign protocols for catalytic asymmetric synthesis and even the spectroscopic detection of catalytically active intermediates. Using this new system, a large variety of substrates were hydroformylated in scCO 2 with rates and enantioselectivities comparable to those of the parent system in benzene solution. At the same time, the CO 2 -philic substitution pattern resulted in a significantly higher regioselectivity towards the desired chiral aldehydes. Preliminary results indicated for the first time also a remarkable potential of BINAPHOS-derived ligands for asymmetric hydrogenation reactions. The possibility to develop new work-up schemes for product purification and/or catalyst immobilisation based on scCO 2 as the only medium for catalysis and extraction (CESS process) was experimentally verified using a rhodium catalyst containing 10 .

Enantioselective Hydrogenation with Racemic and Enantiopure Binap in the Presence of a Chiral Ionic Liquid

There is growing interest in the use of chiral ionic liquids (cILs) in asymmetric catalysis as the reaction media or as an additive. Whereas chiral solvents have shown limited success in enantioselective synthesis, the use of cILs have recently resulted in generating significant enantioselectivity in organocatalysis, heterogeneous catalysis, and transition-metal-catalyzed reactions. As part of our interest in this area, we investigated the Rh-catalyzed homogeneous hydrogenation in amino-acid-derived cILs. Product enantioselectivities up to 69% ee were obtained by using rhodium catalysts derived from tropoisomeric phosphine ligands in combination with cILs as the only source of fixed chirality. Herein we report for the first time that cILs can be used to induce high levels of enantioselectivity when combined with racemic catalysts; the product enantioselectivites obtained are as high as those obtained with the corresponding enantiomerically pure ligand. We provide experimental evidence that the key role of the cIL is to effectively block the catalytic cycle for one of the two enantiomers of the catalyst (chiral poisoning). In addition, the cIL can amplify and even reverse the enantioselectivity of a given enantiopure ligand in comparison to the reaction in organic solvents. Binap (2,2’-bis(diphenylphosphanyl)-1,1’-binaphthyl) was selected as a prototypical ligand as it has a broad range of possible applications. The rhodium-catalyzed hydrogenation of dimethyl itaconate (S1) and methyl N-acetamido acrylate (S2) were chosen as benchmark reactions (Scheme 1). Under conventional conditions, enantiomerically pure (S)-binap leads to only moderate enantioselectivities (P1: 67% ee, (S); P2 : 21–25% ee, (R)) in these transformations, thus providing a sensitive diagnostic tool for the effectiveness of the cIL. Themethyl ester of (S)-proline was used as the source of chirality in the cIL ([MeProl][NTf2]), which has already proved successful in case of the tropoiosmeric ligands. The hydrogenation of S1 was carried out under a set of standard reaction conditions employing a 5:1 mixture of CH2Cl2 and [MeProl][NTf2] as the reaction medium. By using a rhodium catalyst, formed in situ from [Rh(acac)(cod)] (A ; acac= acetylacetonate, cod= 1,5-cyclooctadiene) and racemic binap, (S)-2-methyl-succinic acid dimethyl ester ((S)-P1) was obtained quantitatively with an enantioselectivity of 67% ee (Table 1, entry 1). Almost the same enantioselectivity was achieved with complex B as the rhodium source (Table 1, entry 2). These results demonstrate that an identical level of enantiodifferentiation can be achieved with the combination of racemic binap and [MeProl][NTf2], compared to that obtained with a single enantiomer of the chiral ligand. In the case of substrate S1, the presence of the cIL does not affect the principle mode of enantiodifferentiation of the chiral ligand. This is demonstrated by the observation that the use of enantiomerically pure (R)-binap leads to enantioselectivities of 66–71% for (R)-P1 in the presence of [MeProl][NTf2] (Table 1, entry 3 and 4). The use of (S)-binap results in (S)-P1 having almost identical enantioselectivities of 64–70%

Continuous Enantioselective Hydrogenation with a Molecular Catalyst in Supported Ionic Liquid Phase under Supercritical CO2 Flow

The synthesis of enantiopure compounds using chiral transition-metal catalysts is largely dominated by batchwise procedures. [1] This typically results in considerable amounts of solvent waste from both reaction and purification steps, low space–time yields, and often precludes reuse of the precious catalyst. [2] The development of efficient and flexible flow systems could provide alternative modes of operation, combining the benefits of an integrated reaction and purification strategy with the molecular approach to catalyst design. Efficient immobilization of chiral catalysts in a liquid-like environment is an important prerequisite for the successful implementation of this strategy. [3] The concept of supported ionic liquid phase (SILP) catalysis describes a molecular catalyst that is dissolved in a small amount of an ionic liquid (IL) that is immobilized on the surface of a solid support, typically a porous oxidic material such as silica or alumina. Physisorption and capillary forces lead to surface coating and pore filling, yielding free-flowing powders that can be used in fixed or fluidized bed reactors. [4, 5] Due to a mean film thickness in the range of 10–20 �, catalysts dissolved in the supported layer are close to a large interface, and diffusion pathways are reduced in comparison to bulk biphasic systems, often leading to high reaction rates. [6–10] Despite their proximity to the surface, the molecular catalysts in the nanoliquid confinement of SILPs have been shown by kinetic analyses to perform in a genuinely homogeneous manner. [5–7] The ease of preparation and the modularity of SILP catalysts contribute to making them ideal candidates for continuous catalysis, combining many advantages of both homogeneous and heterogeneous systems. For a stable and efficient process, the choice of the mobile phase is decisive. SILP catalysts containing an organometallic complex have been applied successfully in continuous-flow catalysis involving gaseous substrates with moderate [11] to good stability. [12, 13] This approach is, however, restricted to volatile substrates and catalysts of sufficient thermal stability. Non-IL-miscible liquid phases would allow for milder reaction conditions and broaden the substrate scope to more interesting molecules, but usually lead to progressive desorption of the SILP by abrasion or gradual dissolution. [8, 14, 15] Cole-Hamilton and co-workers have recently demonstrated that supercritical carbon dioxide (scCO2) can be used as a mobile phase to transport nonvolatile substrates and products continuously over organometallic SILP catalysts for the hydroformylation of long-chain olefins. [16] By the combination of SILP catalysis with scCO2 flow, high activity paired with excellent stability could be achieved. [17] The infinitesimal solubility of ILs in scCO2 [18] allowed for retention of the SILP while organic products were continuously extracted. [19] A similar approach was recently described by the team of Iborra and Lozano for continuous-flow kinetic resolution of alcohols by using the lipase CAL-B in a SILP-type system and CO2 as the mobile phase. [20]

A Fully Integrated Continuous‐Flow System for Asymmetric Catalysis: Enantioselective Hydrogenation with Supported Ionic Liquid Phase Catalysts Using Supercritical CO2 as the Mobile Phase

A continuous-flow process based on a chiral transition-metal complex in a supported ionic liquid phase (SILP) with supercritical carbon dioxide (scCO(2)) as the mobile phase is presented for asymmetric catalytic transformations of low-volatility organic substrates at mild reaction temperatures. Enantioselectivity of >99% ee and quantitative conversion were achieved in the hydrogenation of dimethylitaconate for up to 30 h, reaching turnover numbers beyond 100000 for the chiral QUINAPHOS-rhodium complex. By using an automated high-pressure continuous-flow setup, the product was isolated in analytically pure form without the use of any organic co-solvent and with no detectable catalyst leaching. Phase-behaviour studies and high-pressure NMR spectroscopy assisted the localisation of optimum process parameters by quantification of substrate partitioning between the IL and scCO(2). Fundamental insight into the molecular interactions of the metal complex, ionic liquid and the surface of the support in working SILP catalyst materials was gained by means of systematic variations, spectroscopic studies and labelling experiments. In concert, the obtained results provided a rationale for avoiding progressive long-term deactivation. The optimised system reached stable selectivities and productivities that correspond to 0.7 kgL(-1)h(-1) space-time yield and at least 100 kg product per gram of rhodium, thus making such processes attractive for larger-scale application.

Quinaphos and Dihydro‐Quinaphos Phosphine–Phosphoramidite Ligands for Asymmetric Hydrogenation

New derivatives of the Quinaphos ligands and the related Dihydro-Quinaphos ligands based on the more flexible 1,2,3,4-tetrahydroquinoline backbone have been prepared and fully characterised. A general and straightforward separation protocol was devised, which allowed for the gram-scale isolation of the R(a),S(c) and S(a),R(c) diastereomers. These new phosphine-phosphoramidite ligands have been applied in the Rh-catalysed asymmetric hydrogenation of functionalised olefins with the achievement of excellent enantioselectivities (> or = 99%) in most cases and turnover frequency (TOF) values of up to > or = 20,000 h(-1). These results substantiate the practical utility of readily accessible Quinaphos-type ligands, which belong to the most active and selective category of ligands for Rh-catalysed hydrogenation known to date.

Highly Enantioselective Rh‐Catalysed Hydrogenation of 1‐Alkyl Vinyl Esters Using Phosphine–Phosphoramidite Ligands

MatPhos, a good mate for hard tasks: The asymmetric hydrogenation of 1-alkyl vinyl esters, thwarted so far by mediocre ee values and low activities, can now be achieved with MatPhos/Rh catalysts with ee values of 96-99% for a variety of substrates at low catalyst loadings (0.1-1 mol %) and under mild conditions (5-20 bar H2, room temperature). After hydrolysis, the corresponding chiral secondary alkyl alcohols can be obtained in high enantiopurities providing a general and practical route to this important product class.

Highly regio- and enantio-selective rhodium-catalysed asymmetric hydroformylation without organic solvents

High enantioselectivity and unprecedented high regioselectivity without the need for hazardous organic solvents are achieved in rhodium-catalysed asymmetric hydroformylation with the perfluoroalkyl-substituted ligand (R,S)-3-H2F6-BINAPHOS, whereby the substitution pattern of the ligand is crucial for its successful use in compressed carbon dioxide and for the increased regioselectivity.

Continuous-flow homogeneous catalysis using the temperature-controlled solvent properties of supercritical carbon dioxide

A fully integrated continuous process for homogeneous catalysed reactions in scCO(2) has been developed exploiting the tunable solvent properties of scCO(2). A heated condenser situated above the reaction zone leads to a phase split under isobaric conditions resulting in efficient catalyst retention and recirculation. Continuous isomerisation of allylic alcohols was carried out for over 200 hours time-on-stream demonstrating the viability of this approach.

Palladium(II) and platinum(II) complexes containing new phosphinoxy chiral P,N-ligands

Abstract The chiral diphenylphosphinoxy P,N-ligands (+)-(2S,3R)-4-dimethylamino-3-methyl-1,2-diphenyl-2-diphenylphophinoxybutane (2) and (+)-(1S,2R)-2-dimethyl-amino-1-phenyl-1-diphenylphosphinoxy-propane (3) have been prepared starting from the corresponding aminoalcohols. The reactions of the already reported ligand 2[1-phosphinoxy-1-(1S,2S,5R)-menthyl]pyridine (1) and of 2 and 3 with palladium(II) and platinum(II) substrates have been studied. The palladium complexes [Pd(1–3)Cl2] have been used as catalytic precursors in the asymmetric Grignard cross-coupling reaction between 1-phenylethyl magnesium bromide and vinyl bromide. Some considerations on the low enantioselectivity found using the phosphinoxy P,N-ligands 1–3 are proposed. With the aim of verifying diastereoselectivity in the nucleophilic substitution reactions at palladium(II) and platinum(II) complexes containing the P,N-ligands 1–3, the reactions of the complexes 5, 6, 7 and 10 with the Grignard reagent PhMeCHMgBr, in the racemic form, have been unsuccessfully undertaken. The X-ray crystal structures of [Pt(3)(Ph2PO)Cl], 10, and of the oxide of 1 are also reported.

NOBIN-based phosphoramidite and phosphorodiamidite ligands and their use in asymmetric nickel-catalysed hydrovinylation

Phosphoramidite and P-stereogenic phosphorodiamidite ligands derived from (Sa)-2-phenylamino-2′-hydroxy-1,1′-binaphthyl (N-Ph-NOBIN) and bis(1-phenyl-ethyl)amine were synthesised, fully characterised, and the absolute configuration of the stereogenic phosphorus atoms was assigned. The phosphoramidite ligand L2 features three non-bridged substituents at phosphorus comprising the bis(1-phenylethyl)amine and two NOBIN moieties. The NOBIN units are bound to the phosphorus through the oxygen atoms with two pendant nitrogen atoms. In the Ni-catalysed hydrovinylation of styrene no conversion was observed with the phosphorodiamidites, while the phosphoramidite ligands led to active catalysts with a marked co-operative effect on selectivities. Whereas the racemic product was obtained with the (Sa,Sa,SC,SC) diastereomer, the (Sa,Sa,RC,RC) diastereomer proved to be one of the best ligands for this reaction, leading to almost perfect selectivity and ees of up to 91%.